Natural killer cells are involved in allo immune reaction. Specific NK cells subsets are related to tolerance while others are related to chronic AB mediated rejection and graft loss.
Cytolytic effector activity of NK cells are produced through direct lysis and AB dependent cellular toxicity.
NK cells have antiviral and antitumor effects
increased post Tx incidence of malignancy and infection could be explained by effect of immunosuppression on NK cells.
References:
Pontrelli, P et al : The role of natural killer cells in the immune response in kidney transplantation, Front. Immunol ,2020,11:1454
Wael Hassan
3 years ago
natural killer sub type of T lymphocyte that can attack foreign AG as apart of cellular immunity and it also can lyse AG-AB complex (no need for APC to be activated)
its role in graft rejection mostly cellular rejection as it not need APC to recognize graft so it has a rapid action if no good induction to deplete it , it also help in humoral rejection as it secret inflamatory cytokines
Mohamed Essmat
3 years ago
Natural killer cells are considered a subtype of lymphocytes but are part of innate immunity They represent around 5-10% of peripheral circulating lymphocytes They carry stimulatory signals and inhibitory signals that bind to cells by multiple ligands and the net balance decided its action thus antigen on APC isn’t needed for activation. NK cells stimulation elicit it’s action through 3 main ways: *Direct cell lysis: switch into cytotoxic NKCs and cause destruction of cell membrane. *Complement dependent cytotoxicity
*Secretion of Inflammatory cytokines causing macrophages and dendritic cells migration and naïve T-cell maturation into Th1 which leads to adaptive immunity involvement. They play an important role in graft rejection and tolerance * NK switching to cytotoxic NK cause graft destruction, more exposure of alloantigen ,involvement of adaptive immunity both cellular and humoral eventually causing ABMR. *NKCs attack donor derived APC post-transplant and inhibit direct pathway stimulation of immunity which usually associated with acute rejection post-transplant also NKreg secrets IL-10 which elicit inhibitory effect on adaptive immunity.
Abdullah Raoof
3 years ago
Natural Killer Cells
Another participant in the alloimmune response is the NK cell. NK cells are lymphoid cells that do not carry TCRs or
BCRs but instead express complementary activating and inhibitory receptors. Activating receptors recognize ligands
induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class I
molecules. NK cells are stimulated when the balance between activating and inhibitory signals is tilted in favor of the
former. Since allograft tissues express nonself MHC proteins, they do not engage inhibitory receptors on donor NK,
leading to NK-cell activation. Therefore, in contrast to alloreactive T and B lymphocytes which respond to nonself,
NK cells respond to missing self. NK cells that infiltrate allografts can also be activated by binding of alloantibodies
in the graft to FcRs on NK cells. Once activated, NK cells kill their targets by secreting the same molecules utilized
by CTL (perforin, granzyme, and IFNy) and differentiate to memory cells. Despite their cytotoxic and memory
functions, NK cells appear to have a secondary role in allograft rejection. Their most conspicuous role in immunity is
in the setting of viral infection. Infected cells are rapidly detected by NK cells because of diminished MHC class I
expression and increased expression of activating ligands.
GABRIEL M. DANOVICH ,HANDBOOK OF KIDNEY TRANSPLANTATION ,
AMAL Anan
3 years ago
Natural killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5–10% of circulating lymphocytes. NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect .NK cells represent one of the main cellular components of innate immunity along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. They mediate immune responses against intracellular pathogens representing key mediators of the anti-viral and anti-neoplastic defense, but they also play a key role, through the production and release of several cytokines, in many inflammatory diseases, including acute and chronic kidney diseases.Interestingly, the role of this lymphocyte subset in the progression of kidney injury is starting to be uncovered .
The NK cells accomplish their cytolytic effector activity through
two main mechanisms of action :
*Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
*Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
In both cases, the lytic function of NK cells depends upon cytolytic molecules, mainly granzyme and perforin, and their activation leads to the production of several inflammatory cytokines . Granzyme and perforin are included into cytoplasmic lytic granules, characterized by several lysosomal-associated membrane glycoproteins (LAMPs) into the lipid bilayer. These proteins appear on cell surface after cytotoxic granules exocytosis . Among the different LAMPs, CD107a/LAMP-1 has been widely used as a functional marker to identify NK cell activity, since its expression is significantly higher on the surface of NK cells after MHC stimulation and correlates with both cytokine secretion and NK cell-mediated lysis of target cells .Interestingly, Conehn et al. demonstrated that CD107a/LAMP-1 protects NK cells from self-destruction upon target cell killing, since CD107a/LAMP-1 deficiency, both in human and in mice NK cells, increased NK cell apoptosis after degranulation .
The interaction of NK cells with the target cell can occur through distinct inhibitory or stimulatory receptors and, therefore, defines the fate of the target cell . Normal cells are protected from NK cell killing since stimulatory receptors signals are balanced by inhibitory receptors signals coming from the interaction with the self-molecules of the MHC class I complex. Neoplastic transformation or cellular infection can induce the expression of stimulatory ligands that overcome the inhibition induced by inhibitory receptors. In this case, an induced-cell recognition occurs . In many contexts both missing-self and induced-self recognition are likely to operate simultaneously to provide to NK cells the maximum ability to discriminate normal cells from transformed or infected ones.
NK cells can express on their surface different receptors able to recognize several polymorphic variants of MHC I molecules. Indeed, the human NK cell receptor repertoire is highly complex in each individual . In addition, NK cells express specific stimulatory and inhibitory receptors for various other ligands present on the surface of the target cells and the balance of inhibitory and stimulatory signals received by a NK cell determines the outcome of its interactions with target cells . These signals involve immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules and inhibitory receptors, other stimulatory receptors and adhesion molecules, such as KIR, immunoglobulin-like transcript (LIR), leukocyte-associated immunoglobulin-like receptor (LAIR), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM) . Thus, the activation program of NK cells derives from the integration of activator and inhibitor signals, which varies according to the nature of the interacting cells. In addition, NK cells also express cytokines and chemokines receptors that are crucial for the regulation of NK cell functions and Toll like receptors that mediate the production of IFN-g and increase cytotoxicity.
References:
1. Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57. 10.1038/nri3044 .
2. Turner JE, Rickassel C, Healy H, Kassianos AJ. Natural killer cells in kidney health and disease. Front Immunol. (2019) 10:587. 10.3389/fimmu.2019.00587.
3. Hoffmann U, Neudörfl C, Daemen K, Keil J, Stevanovic-Meyer M, Lehner F, et al. . NK cells of kidney transplant recipients display an activated phenotype that is influenced by immunosuppression and pathological staging. PLoS ONE. (2015) 10:e0132484. 10.1371/journal.pone.0132484.
4. Trojan K, Zhu L, Aly M, Weimer R, Bulut N, Morath C, et al. . Association of peripheral NK cell counts with Helios + IFN-γ(-)T(regs) in patients with good long-term renal allograft function. Clin Exp Immunol. (2017) 188:467–79. 10.1111/cei.12945 .
5. Turner JE, Becker M, Mittrücker HW, Panzer U. Tissue-resident lymphocytes in the kidney. J Am Soc Nephrol. (2018) 29:389–99. 10.1681/ASN.2017060599 .
Last edited 3 years ago by AMAL Anan
AMAL Anan
3 years ago
Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
NK cells were originally described as large granular lymphocytes with natural cytotoxicity against tumor cells. NK cells were later recognized as a separate lymphocyte lineage, with both cytotoxicity and cytokine-producing effector functions1. The acquisition of cell cytotoxicity during evolution has been associated with the development of highly sophisticated and robust mechanisms that control the initiation of the cytolytic processes and avoid tissue damage. Along this line, much progress has been made over the last fifteen years in the dissection of the mechanisms that allow NK cells to discriminate target cells from other healthy ‘self’ cells. These data have been instrumental in defining several recognition strategies and in the emergence of the ‘dynamic equilibrium concept’. The NK cell detection system includes a variety of cell surface activating and inhibitory receptors, the engagement of which regulates NK cell activities. Thus, the integration of antagonistic pathways upon interaction with neighboring cells governs the dynamic equilibrium regulating NK cell activation and dictates whether or not NK cells are activated to kill target cells2.
References:
1-Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989). Vivier, E., Nunes, J.A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).
2-Lanier, L.L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005). Sivori, S. et al. CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and den- dritic cells. Proc. Natl. Acad. Sci. USA 101, 10116–10121 (2004).
3-Gerosa, F. et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 (2005).
4-Hart, O.M., Athie-Morales, V., O’Connor, G.M. & Gardiner, C.M. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-γ production. J. Immunol. 175, 1636–1642 (2005).
Ahmed mehlis
3 years ago
●Definition:
Natural killer cells (also known as NK cells, K cells, and killer cells) are a type of lymphocyte (a white blood cell) and a component of innate immune system.
●Apotosis Vs cell lysis :
NK cells are cytotoxic; small granules in their cytoplasm contain special proteins such as perforin and proteases known as granzymes.
Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter, inducing apoptosis.
The distinction between apoptosis and cell lysis is important in immunology – lysing a virus-infected cell would only release the virions, whereas apoptosis leads to destruction of the virus inside.
●role in transplantation?
Natural killer cells play an important role in the human immune system, as they are involved in recognizing and killing harmful cells such as tumor cells. These harmful cells sometimes attempt to escape immune detection by decreasing MHC proteins, which are proteins expressed on cells that allow T cells to bind to, recognize, and tolerate itself. This mechanism renders the harmful cells invisible to T cells, but not to natural killer cells. Through their KIR receptors, natural killer cells can detect the absence of these MHC proteins and therefore kill the harmful cells. This constitutes a very important role.
Immune cells called natural killer cells contribute to organ rejection after transplantation because they miss “self” proteins on donor cells, according to a study appearing in an upcoming issue of JASN. A better understanding of this process may help clinicians prevent and treat organ rejection.
Transplanted organs are recognized by the immune system of the recipient as foreign or non-self, which leads to rejection of the organs. Rejection is prevented or treated with drugs that suppress the immune system, mostly targeting T immune cells; however, rejection can still occur despite such treatment, not only because T cells may not be completely suppressed by the therapy, but also because of antibodies and “natural killer cells” that target the donor tissue.
Natural killer cells play an important role in the human immune system, as they are involved in recognizing and killing harmful cells such as tumor cells. These harmful cells sometimes attempt to escape immune detection by decreasing MHC proteins, which are proteins expressed on cells that allow T cells to bind to, recognize, and tolerate itself. This mechanism renders the harmful cells invisible to T cells, but not to natural killer cells. Through their KIR receptors, natural killer cells can detect the absence of these MHC proteins and therefore kill the harmful cells. This constitutes a very important defense mechanism.
In transplantation, the donor cells in the transplanted organ are not escaping immune detection by decreasing MHC expression, but these donor cells express different MHC proteins than the recipient. The natural killer cells of the recipient therefore miss the “self” MHC on these donor cells and become active.
“This is exactly what we found in the study of 924 kidney transplantations: that the ‘missing self’ predicted by genetic analyses of the MHC molecules of donors and recipients, and the genetically determined KIR repertoire of the recipients, is predictive of rejection in kidney transplant biopsies,” said senior author Maarten Naesens, MD, PhD, of KU Leuven, in Belgium. “Therefore, the study shows that genotyping the donors and recipients not only for MHC (as is done in routine clinical practice), but also for KIR, will enable us to assess the presence or absence of ‘missing self,’ and improve the risk assessment of kidney transplant rejection.
●Reference: Callemeyn J, Senev A, Coemans M, et al. missing self–induced microvascular rejection of kidney allografts: a population-based study. JASN. 2021. doi: 10.1681/ASN.2020111558
Mohammed Sobair
3 years ago
NK cells:
are a component of the innate immune system that use a combination of
activating and inhibiting receptors specific for HLA class I molecules to differentiate
between autologous and allogeneic cells, thereby controlling their activation in response
to foreign tissues .
When activated, NK cells produce cytotoxic effector molecules without the need for
priming by antigen presenting cells.
This process takes place before the engagement his process takes place before the
engagement of adaptive immune system.
They are 5–20% of lymphocytes in the spleen, liver, and peripheral blood and are
present at lower frequencies in the bone marrow, thymus, and lymph nodes.
Studies in mice have shown that NK cells can undergo clonal expansion to create innate
Memory, analogous to memory responses of the adaptive immune system.
Role of NK cell in transplant is controversy, recently NK cells show contribution to the
rejection of kidney and lung transplants. Infiltration of kidney allografts by cytotoxic
CD56+ cells producing high amounts of granzyme A and B and interferon-gamma has
been identified as a feature of acute rejections in kidney transplants.(1).
They mediate the antibody-dependent cellular cytotoxicity (ADCC) of targets through
FcγRIII.(CD16), a receptor that binds the Fc portion of antibodies.
Functional aspects of NK in mediating allograft tolerance:
Host NK cells, through their killing of allogeneic APCs, limit the persistence of donor-
derived DCs, therefore contributing to the induction of transplant tolerance.
NK cells and immunosuppressive drugs:
as it has recently been demonstrated that steroids and Calcineurin inhibitors limit the
organ transplantation .Transplant international .03 August 2009.
Theepa Mariamutu
3 years ago
Natural killer cells
• effector lymphocytes deriving from common lymphoid progenitors
• represents 5-10% of circulating lymphocytes
• natural cytotoxic cells but do not require antigen exposure in mediating effect
• accomplish cytolytic effector activity through 2 mechanism
o Direct lysis -recognition of HLA class 1 molecules by KIR( killer cells immunoglobulin-like receptors), inhibitory receptors on NK cell inhibits cytotoxic activity and maintains the recognition of self
o Antibody dependant cellular cytotoxicity (ADCC)- interaction between Fc receptor FcγRIII (CD16) expressed on NK cells and Fc fragment of apsn antibody recognising foreign antigens on target cells induces lysis of these cells
NK cells in Kidney Transplantation
• Are heterogenous population of innate lymphocytes with subset-specific functional roles and with complex functions during haemostatic and pathological conditions
• Still controversial in role in immune reactivity to solid organ transplantation
• May promote allograft injury
• Evidences showed that may play a important role in the priming of allograft tolerance
• Post transplantation, NK cell subsets can transform at the peripheral level which not able to do by pre transplant cells and these transformation will affect both the number and the phenotype, so this explains that NK cell immunoregulatory characteristic can influence the graft outcome
NK cells involvement in Acute or chronic allograft rejection
ABMR
• Yagisawa et al showed presence of both NK cell and DSA induced acute kidney graft rejection in a mice model of kidney transplantation, but DSA alone can may lead to late graft failure but not acute mediated rejection
• Influence maturation of DCs and lead to activation of T cells
• NK cell are early source of Th1-type immune response induced by IFN-g
• directly interact with CD4+ T lymphocytes leads to reactivity and induction of acute rejection pathway
• Human ABMR through CD16 expression which triggered by anti-HLA antibodies (DSAs) contributed to graft loss- proposed by Turner et al
• Nk cells have been identified in peritubular capillaries and DSA seen bind to the graft endothelial cells of the biopsies of ABMR
• AMBR showed increased CD56bright and CD56dim
TCMR
• IHC of the graft showed TCMR is characterised by higher number of CD56+ and CD57+ cells within the interstitial compartment associated with interstitial and tubulitis – 0.56cells/mm2 both interstitial and glomerular level associated with worse graft outcome
• Biopsies from patient T cell have shown increased absolute number of CD 56 bright
• CD56bright NK cells has role in TCMR trough secretion of pro inflammatory molecules such IFN-g,leads to increase recruitment of alloreactive T cells and up regulate MHC 1&2 on graft target cells making more prone for cytotoxic killing
NK cells in influencing transplant tolerance
• NK cells have potent immunoregulatory properties that induces tolerance
• Skin transplantation model in mice- recipient NK cell can contribute to the induction of graft tolerance by killing APC
• Activated NK cells can destroy donor derived DCs through direct lysis mechanism lead to tolerance indiction
• IL-10 produced by NK cells could have role in maintenance of transplant tolerance
References
Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L. and Stallone, G., 2020. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Frontiers in Immunology, 11.
Kidney Transplantation: Principles and practice by Stuart J.Knechtle
Ibrahim Omar
3 years ago
NK cells are subsets of circulating lymphocytes (5-20%).
they are the predominant lymphocytes mediating the innate immune responce.
they mediate 2 major functions; anti-tumor and anti-viral actions.
they express 2 main cell receptors. the 1st one is CD16 that binds to the Fc component of anti-bodies reacting with different antigens expressed on antigen presenting cells. these antigens are mostly made from tumors and viral components, explaining the role of NK cells in eradication of malignant cells and virus-infected cells. also, NK cells have been a target of cancer immunotherapy. CD16 also mediates chronic anti-body mediated rejection and has a suggested major role in develoment of tolerance. the 2nd one is CD56 that mediates an inflamatory reaction as it is a pro-inflamtory mediator.
the role of NK cells in transplant is still controversial. NK cells inhibition by immunosuppressives as post-transplantation, mediate the development of some malignancies. also, their role in graft tolerance is attractive for a possible better graft survival by handling the various actions of these cells.
Dalia Ali
3 years ago
Natural killer cells (NK) are lymphocytes involved in innate immune response. NK regulate the allo-immune response in kidney transplant recipients.
Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss.NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Paola Pontrelli P ,Federica Rascio F. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 23 July 2020
Ben Lomatayo
3 years ago
NK cells are part of the innate immune system. It from lymphoid progenitor together with T and B lymphocytes. They enhance B and T cells responses, and they have specific anti-cancer and anti-viral activities.
Mahmoud Rabie
3 years ago
NK cells are effector lymphocytes and account 10-15% of circulating lymphocytes and don not need antigen exposure for their activation unlike the cytotoxic T cells.
Role of NK cells in transplantation varies from rejection to tolerance. NK cells play a role in both T cell mediated rejection and antibody mediated rejection.CD56 bright NK cells are able to secrete proinflammatory molecules such as IFN-g which play a role in TCMR while CD56 dim / CD 16 NK cells can interact with DSA in the graft endothelial cells activating the Antibody dependant cellular cytotoxicity and hence ABMR. On the other hand, NK cells and Treg can activate each other promoting tolerance and also the activated NK cells have the ability to kill the dendritic cells increasing the potential of tolerance.
Immunosuppressive drugs have the ability to change the phenotype of NK cells and also reduce their number post transplantation so follow up of NK cells number and function can predict the risk of infection and malignancy post transplantation.
Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. They have a role in anti-viral and anti-tumor defense mechanism , they also regulate several aspects of the allo-immune response in kidney transplant recipients. NK cells have a key role in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Reference:
The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation
Paola Pontrelli, Federica Rascio, […], and Giovanni Stallone
fakhriya Alalawi
3 years ago
NK (natural killer) cells are lymphocyte-like cells capable of killing some targets, notably virus-infected cells and tumor cells. Natural killer cells share features of both lymphocytes and innate immune cells. New studies show that NK cells can discriminate between self and foreign tissues and play a key role in the initiation and regulation of adaptive immune responses after solid organ transplantation.
Natural killer (NK) cells are of special interest because, in addition to cytokine production, NK cells can directly target the transplanted tissue through the balance of activating and inhibitory receptors and their ligands expressed or not expressed by the graft. In solid organ transplantation (SOT), the inhibitory KIRs expressed by NK cells can bind to the corresponding MHC-I expressed by the graft which prevents NK cell activation. The absence of the cognate MHC-I ligand induces a ‘missing self-situation’ and activated NK cells target the graft. However, more recent studies demonstrate that NK cells become activated early after organ transplantation and can contribute to the cell-mediated alloresponse and acute rejection process.
The mechanism of NK cell alloreactivity is also mediated by an indirect pathway, i.e. through the production of pro-inflammatory cytokines. The secretion of IFN- and TNF- by NK cells is likely to induce and upregulate the expression of MHC molecules and costimulatory receptors on APCs, thus promoting the maturation efficacy of professional APCs (dendritic cells and B cells) and presumably nonprofessional APCs (endothelial cells) which enhance direct and indirect alloresponses by T cells. NK cells can also kill Foxp3+ regulatory T cells, depending on the activation status of NK cells.
More recently, NK cells have been shown to be crucial for graft survival. CD28-deficient mice readily reject an MHC mismatched heart allograft; in this model, rejection can be prevented by the depletion of host NK cells. Currently, there is no doubt that NK cells can contribute to acute and chronic allograft rejection in rodent models. In human SOT, the exploration of NK cells is much more limited. The presence of NK cells in kidney biopsy of acute cellular rejection is rare, but recent data demonstrate that NK cells and macrophages are selectively increased in peritubular capillaries of kidney biopsies following antibody-mediated rejection situations.
The absence of inhibition with the presence of an activating receptor induces the killing of the allogeneic tissue. The combination of activating or inhibitory KIRs defined by A or B haplotype and the expression of their cognate MHC ligands can theoretically lead to alloreactivity potential against the graft. Recent publications have shown a correlation between specific KIR/HLA-C and graft survival in kidney and liver transplantation.
References:
1. Villard J. The role of natural killer cells in human solid organ and tissue transplantation. Journal of innate immunity. 2011;3(4):395-402.
2. Maier S, Tertilt C, Chambron N, Gerauer K, Huser N, Heidecke CD, Pfeffer K: Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28–/– mice. Nat Med 2001;7:557–562
Ramy Elshahat
3 years ago
What are the NK cells?
NK cells are subtype of lymphocytes but part of innate immunity
They represent around 5-10% of peripheral circulating lymphocytes
And it get maturation in 2ry lymphoid organ and divided into 3subtypes according to Cd 56/Cd 11b/Cd27 Rc exposed on its surface
NK1:Cd 56 dim/Cd11b +ve/Cd 27-ve…it secrets proinflammatory cytokines and play role in graft rejection
NK2:Cd56bright/Cd11b-ve/Cd27-ve
NKreg: Cd56bright Cd11b-ve Cd27+ve and secrets IL10 and play role in tolerance
What’s it’s role in immune system
NK cells don’t need Ag on APC to get activated.it carry stimulatory singals and inhibitory signals bind to cells by multiple ligands and the net balance decided its action
Usually NK interact with self class 1 HLA on self cells which stimulate the inhibitory signals and absence of self HLA class 1 like on damaged cell/neoplasm cell/virally infected cells (after HLA class 1 downregulation) lead to NK stimulation which elicit it’s action through 3 main mechanisms
1/direct cell lysis: switch to cytotoxic Nk and cause destruction of cell membrane
2/complement dependent cellular cytotoxicity: antibodies attachment to foreign HLA and Nk attach to fc region through cd16(fCyR111) activating its cytotoxicity
3/it secrets inflammatory cytokines like interferone gamma causing macrophages and denderitic cells migration also Naive t cell maturation into Th1 which leads to adaptive immunity involvement.
Role of kidney tranplantation
Play important role in graft rejection/tolerance/immune system monitoring
1)graft rejection: NK switching to cytotoxic Nk cause graft destruction and more exposure of alloantigen also invasion of macrophages and maturation of Naive tcell into effector Th1 and involvement of adaptive immunity both cellular and humoral immunity.also IgG elicit part of it’s action by Nk after bind between fc region and cd16 causing C4d negative (independent) ABMR
Graft tolerance:it attack and destroy donor derived APC post transplant and inhibit direct pathway stimulation of immunity which usually associated with acute rejection post transplant also NKreg secrets IL10 which elicit inhibitory effect on adaptive immunity.
Immunosuppressant medications monitoring:CNI cause decrease NK number and mTOR cause change in it’s phenotyping and it’s function and cytokines secretion which lead to increase risk of infection and malignancy
Studies are ongoing to monitor Nk number and function to be used as a sensor to drugs doses in the future.
Reference:
1-Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cell in the immune response in kidney transplantation. Front Immunol 2020;11:1454.
2- Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235:286
3- Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2:735.
4- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
Thank you Rami please try to organize your information like so:
name of cell
Origin
Mechanism of action
Related to rejection,which type ,tolerance,accommodation,monitoring,
Mechanism of each controlling drug and cotrevesial action.
Mahmud Islam
3 years ago
Natural killer cells (NK) as the name implies they have a direct cytotoxic effect on the target, no need for antigens. In addition to their antiviral and anti-tumor effects, they play a role in alloimmune response in kidney recipients. Natural killer cells (NK) represent a population of lymphocytes involved in the innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the alloimmune response in kidney transplant recipients. They accomplish cytolytic activity either by direct lysis or antibody-dependent cellular cytotoxicity They have KIR (killer cell immunoglobulin-like receptor) which recognizes HLA class I antigens. They express CD16 (FcγRIII) Fc receptor through which the interact with target Fc fragment causing antibody-dependent cellular cytotoxicity.
NK cells are group of lymphocytes which play important role in solid organ transplantation, there are 2 types of NK cells :CD 56 bright and CD 56 dim the dim one comprises 90% of blood and spleen .
NK cells play role in innate immune system also they have defense property against virus and tumor( have the ability to distinguish allogenic cells from self cells) .
NK cells can effect on both T cell mediated rejection (acute or chronic) and Ab mediated rejection .
Natural killer lymphocyte plays an important role in acute and chronic cellar rejection and in antibody mediated rejection and also important in graft tolerance.
NK lymphocyte are cytotoxic cells whose activation doesn’t require antigen to elicits a reaction, unlike cytotoxic T cells . NK cells has inhibitory receptors on the surface , and once this receptor is engaged with HLA class I , it inhibit the Cytotoxic function of the NK cells , so no damage to the self cells . But if NK cells encounter cells that don’t have HLA ( like cancer cells ) they destroy these cells (missing self).
Also NK cells could bound to Fc region of the antibodies and damage cells that bound to the antibody , So NK cells participate in the antibody mediated rejection.
NK cells also secrete INFgamma and TNF that activates T cells , dendritic cells , and macrophages. also secrete many chemotactic factors that attract inflammatory cells toward the graft. (acute and chronic cellular mediated rejection)
On the other hand , NK cells are important in graft tolerance: NK cells can kill APC of the donor, thus preventing these cells from presenting HLA antigens to the T cells , so they prevent T cell activation. Also NK cells produce IL10 which is associated with graft tolerance. Also there is cross talk between NK cells and Treg cells that leads to activation of Treg and induction of graft tolerance.
Reference :
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L and Stallone G (2020) The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol. 11:1454. doi: 10.3389/fimmu.2020.01454
Fatima AlTaher
3 years ago
NK
Represent about 5-10% of circulating lymphoctys , they are important part of innate immune system ,have cytotoxic effect that do not require antigen exposure for stimulation .NK cells can differiate into three types : Natural killer type-1 (NK1) secreting IFN-g , NK type-2 (NK2) producing various cytokines as IL-5 and IL-13 and NK regulatory cells (N K reg ) that has immune regulatory function via cytokines secretion and cell-to-cell contact . Phenotypically , Nk are classified into (high-density CD56bright ( 90% of NK population ) and low density CD56dim cells ( 90 % of all NK population ) that are predominant in prepheral blood , have cytotoxic effects and express high levels of FcγRIII (CD16) so are involved in antibody mediated graft injury (1)
The effect of NK on kidney transplantion is variable , they can induce graft injury and meanwhile may enhance development of operational tolerance.
NK can produce graft injury either
1- Acute graft injury through Antibody-dependent cellular cytotoxicity (ADCC) in presence of DSA through the expression of CD16 or through infiltrate the graft causing direct graft damage.
2- Chronic graft injury as They can enhance migration of immune cells as dendritic cells into the graft producing an increasing alloimmune response as well as enhancing activation of T cells via promoting maturation of dendritic cells and secretion of IFG , this eventually will lead to chronic AMR and chronic graft rejection. NK may exert beneficial effect on graft function through downregulating CD8+ T-cell proliferation by competing for IL15 and they can inhibit clonal expansion of antigen-stimulated T cells as well as killing dendritic cells. (2)
1-Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L., & Stallone, G. (2020). The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Frontiers in immunology, 11, 1454. https://doi.org/10.3389/fimmu.2020.01454 2- Emilie Dugast, Gaëlle David, Romain Oger, Richard Danger, Jean-Paul Judor, et al.. Broad Impairment of Natural Killer Cells from Operationally Tolerant Kidney Transplanted Patients. Frontiers in Immunology, Frontiers, 2017, 8, pp.1721. ⟨10.3389/fimmu.2017.01721⟩. ⟨hal-01712225⟩
Abdulrahman Ishag
3 years ago
What are the NK cells
Nk cells are lymphocytes involved in innate immunity .
The majority are CD8 positive and they variably express NK-cell- associated antigen s ,including CD56 and CD57 .
In the peripheral blood NK cells can express CD4 molecules on their surface.
They do not carry TCR or BCR.
They express complementary receptors . the activating receptors recognize ligands induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class1 molecule.
Allogrft tissure express – non self MHC proteins ,they do not engage inhibitory receptor on the donor NK.
They are either activated by immunoreceptor tyrosine-based activating motifs(ITAMs) or inhibited by immunoreceptor tyrosine-based inhibitory motifs .
NK cells secret a wide variety of cytokines as TNFy,TNFa,Gm_CSF,IL10, IL% and IL13 and chemokines such as MIP-1a ,MIP-1B,IL-8.
TNFa activates macrophage causing cell lysis. Also promote direct NK tumour cell killing.
They have anti viral and anti neoplastic role.
They have short life span of 2 weeks.
Deficiency of NK cells increase the susceptibility to virus infection.
The role of NK in kidney transplantation;
Early activation of NK cells post kidney transplantation is associated with killing of allogenic target cells and release of immune modulatory cytokines and chemkines which can contribute to either rejection or tolerance.
They can activate T-cells through the production of cytokines . They can express Co-stimulatory molecules allowing them to activate T-cells
Transplant rejection usually type 1V hypersensitivity reaction(delayed) mediated by T-cells in which the transplant recipient”s T-cells become alloreactive ,recognizing major MHC antigens on the donated organ and promote local immune and inflammatory responses to defend against the
Referance;
Pmc https//www.ncbi.nlm.nih.gov.
Kidney transplant hand book 6 edition
Nasrin Esfandiar
3 years ago
NK cells are natural cytotoxic cells and part of innate immune system to recognize HLA molecules. They can induce rejection producing IFN-γ, perforin and granzyme by cytotoxic CD56+ cells. Defects of NK cells is producing perforin can induce non-Hodgkin lymphoma as complication of immunosuppression.
Some studies showed that donor NK cells detects HLA class Ι as a result of killer immunoglobulin-like receptors (K1Rs). Their cytotoxic activity is through HLA class recognition by K1Rs and interaction between NK cells CD16 and FC fragment of Abs. Human NK cells are CD3-/CD56+/CD335 (NKp46) mononuclear cells. NK cells can participate in cell mediated or antibody mediated rejection. They can activate T cell and by producing IF-N –γ increase reactivity of CD4+ T cells. A subset of NK cells (NK CD56dim) with CD16 can induce ADCC. Infiltration of CD56+ NK cells is seen in cell-mediated rejection in tubulointerstitium of kidney and confirms role of these cell in T cell rejection. CD56 bright NK cells are important for TCMR by IFN- γ secretion.
NK cell can be active in transplant tolerance. They can kill donor dendritic cells produce IL-10 and influence Tregs. These activities are contributing in tolerance. NK cell can kill allogenic APCs that induce T cell activation. IL-10 can induce regulatory dendritic cells. In tolerant patients NK cells show reduced expression of NKP46 and CD16 that results in reduction of cytotoxicity function and IFN-γ . NK cells are able to induce CD4+ CD25 .FOXP3+ T cells which have regulatory function and can induce tolerance.
References:
1.Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L., & Stallone, G. (2020). The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. In Frontiers in Immunology (Vol. 11).
2.Adenugba, Akinbami PhD1NK Cells in Transplantation, Transplantation: October 2017 – Volume 101 – Issue 10 – p 2262-2264
Heba Wagdy
3 years ago
NK cells represent 5-10% of circulating lymphocytes.
They are one of the components of innate immunity, natural cytotoxic cells that don’t require antigen exposure. (1)
NK cells can contribute in both T cell mediated and antibody mediated rejection. (2)
Antibody mediated rejection:
NK cells influence maturation of dendritic cells and activation of T cells (3)
they secrete IFN-g leading to Th1 immune response and increase the activity of CD4+ T lymphocytes (4)
T cell mediated rejection:
NK cells secrete proinflammatory molecules increase recruitment of alloreactive T cells, upregulate HLA alloantigen (MHC class I and II) on graft cells making them more prone to cytotoxic lysis (5)
NK cells have immunoregulatory functions that may help in allograft tolerance. (6)
NK cells play a role in cancer defense and incidence of cancer increase after transplantation, (7) monitoring NK cells number and function in transplant patients may have a role in controlling and prediction of onset of infection and neoplasia. (8)
The evaluation of number and function of NK cells in peripheral blood of recipients may inform about immune state induced by immunosuppressive drugs and may help to achieve equilibrium between graft survival and reduction of risk of developing malignancies or infections. (9)
(1) Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels
with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57.
(2) Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7.
(3) Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM.
Highlighting the role of DC-NK cell interplay in immunobiology and
immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018).
(4) Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
(5) Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Specialized roles of human natural killer cell subsets in kidney transplant rejection. Front Immunol. (2019) 10:1877
(6) Beike JN, Kuhl NR, Van Kaer L, Gill RG. NK cells promote islet allograft toerance via a perforin-dependent mechanism. Nat Med. (2005) 11:1059– 106.
(7) Grulich AE, van Leeuwen MT, Falser MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-anlysis. Lancet. (2007) 370:59–67. (8) Stallone G, Infante B, Grandaliano G. Management and prevention of posttransplant malignancies in kidney transplant recipients. Clin Kidney J. (2015) 8:637–44. (9) Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The role of natural killer cells in the immune response in kidney transplantation. Frontiers in Immunology. 2020 Jul 23;11:1454.
Nazik Mahmoud
3 years ago
Natural killer cells are lymphoid cells they express complementary activating and inhibitory receptors. It activated when infiltrate the graft by binding of alloantibodies there to fcRs on NK; used to kill their target by performin,granzyme and IFN gama ;they have cytotoxic and memory function mainly in the viral infections.it play secondary role in rejection
Thanks Nazik
Please expand on your answer. No references as well. This is a suboptimal answer
MICHAEL Farag
3 years ago
NK cells are lymphoid cells that do not carry TCRs or BCRs but instead express complementary activating and inhibitory receptors. Activating receptors recognize ligands induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class I molecules.
NK cells are stimulated when the balance between activating and inhibitory signals is tilted in favor of the former. Since allograft tissues express non-self MHC proteins, they
do not engage inhibitory receptors on donor NK, leading to NK-cell activation. Therefore, in contrast to alloreactive T and B lymphocytes which respond to nonself, NK cells respond to missing self.
NK cells that infiltrate allografts can also be activated by binding of alloantibodies in the graft to FcRs on NK cells. Once activated, NK cells kill their targets by secreting the same molecules utilized by CTL (perforin, granzyme, and IFNγ) and differentiate to memory cells. Despite their cytotoxic and memory functions, NK cells appear
to have a secondary role in allograft rejection.
Two subsets of NK cells exist in humans, CD56bright cells and CD56dim cells, with CD56dim NK cells comprising approximately 90% of blood and spleen NK cells. This subset expresses FcγRIIIA (CD16) and undergoes antibody-dependent cell-mediated cytotoxicity (ADCC), the targeted release of cytotoxic molecules in response to FcγR ligation by IgG-opsonized cells.
Thank you for mentioning this fact; “NK cells respond to missing self.” How do you think this is implicated in graft rejection?
Wessam Moustafa
3 years ago
NATURAL killer cells are group of lymphocytes involved in innate immune response
Normally they play key role as anti tumors and antiviral .
After transplantation, they play a key role in graft damage , alloreactive NK cells can direct the adaptive immune response and accumalate other cells thus potentiating immune mediated graft injury leading to eventually chronic Ab mediated rejection and graft loss .
Natural killer cells can infiltrate the graft and causes direct injury
Specific subsets of NK cells may help in graft tolerance .
Transplant immunosuppressive drugs affect NK cells and so increases incidence of post transplant viral infections and malignancy
Assafi Mohammed
3 years ago
Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response.
Role of Natural killer cells (NK):
Having a role in anti-viral and anti-tumor defense.
They also regulate several aspects of the alloimmune response in kidney transplant recipients.
Growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation.
Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss.
NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection.
Activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage.
Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
The NK cells accomplish their cytolytic effector activity through two main mechanisms of action :
1. Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
2. Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
Thanks, well done
I quote this from your reply “ immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection”.
We need a balanced immunosuppression to achieve excellent graft survival while preventing overzealous immunosuppression that leads to increased infection and malignancy.
Amit Sharma
3 years ago
What are the NK cells?
NK cells or the natural killer cells are a subset of circulating lymphocytes representing a component of innate immunity. They constitute approximately 5-10% of the lymphocytes and cause cell lysis. The balance between inhibitory and stimulatory signals on NK cells is responsible for final outcome (cell lysis versus no lysis).
NK cell maturation occurs in medulla of secondary lymphoid organs (lymph node, tonsil, spleen). Mature NK cells are of 3 types depending on the presence or absence of CD56, CD11b and CD27:
1) NK-1: CD56dim CD11b+ CD27-. They have activating role, producing interferon gamma.
2) NK-2: CD56bright CD11b- CD27-. They have inhibitoy role, producing IL-5 and IL-13.
3) NKreg: CD56bright CD27+. They have immune regulatory role via cytokine secretion and cell to cell contact.
What is their role in transplantation?
NK cells have multifaceted roles in kidney transplantation including both in rejection as well as tolerance.
a) Role in rejection: NK cells influence maturation of dendritic cells leading to T cell activation. They also release interferon gamma causing Th1 type response. They interact directly with CD4+ cells leading to increase in their reactivity and acute rejection
DSA bound to graft endothelial cells in peritublar capillaries interact with CD16 on CD56dim NK cells leading to antibody dependent cell-mediated cytotoxicity and antibody mediated rejection.
CD56bright CD57+ NK cells have role in T cell mediated rejection by releasing interferon enhancing the recruitment of alloreactive T cells and HLA antigen to the target cells in graft leading to cytotoxic killing.
b) Role in tolerance: Activated NK cells can directly lead to lysis of donor-derive dendritic cells, ushering in transplant tolerance. Role of increased production of IL-10 by NK cells has also been seen in inducing tolerance.Tolerance due to NK cells has been shown to be relevant especially in first 3 weeks post-transplant.
c) Role with immunosuppression: NK cells act as sensors for immunosuppression. It has been shown that patients on cysclosporin have decreased number of NK cells and decreased CD56dim/ CD56bright ratio at 1 year post traansplant affecting their cytotoxic activity with time. Patients on mTOR inhibitors have been shown to have NK cells with modified degranulation properties with reduced interferon gamma production.
So, in future monitoring NK cell number and their type could become a handy tool to prevent side-effects of immunosuppression like infectiona and malignancies.
Reference:
Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cells in the immune response in kidney transplantation. Fron Immunol 202;11:1454.
Thanks Amit I like your reflection “in future monitoring NK cell number and their type could become a handy tool to prevent side-effects of immunosuppression like infectiona and malignancies”.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
Natural killer (NK) cells have potent effector functions and play
a key role in a range of immune responses, including those against
pathogens and cancers .
NK cells have two key effector functions, which are the cytotoxic lysis of target cells and the release of inflammatory cytokines that amplify the immune response, including interferon (IFN)-c
NK cells provide innate immunity against abnormal cells, where their activation depends on the integration of signals arising from activating and inhibitory receptors on their cell surface.
ROLE OF NATURAL KILLER CELL IN GRAft rejection,
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection
NK cells can also influence maturation of dendritic cells and the subsequent activation of T cells . Moreover, NK cells are an early source of IFN-g, which drive a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes , increasing their reactivity, and these activities can induce acute rejection mechanisms.
despite their essential role in allograft rejection, NK cells might also promote allograft tolerance.
Donor antigen-presenting cells, in the absence of host NK cells, can survive and directly induce the activation of alloreactive T cells that are resistant to co-stimulatory blockade treatment
Thus, in those models in which NK cells have an altered function or are reduced, it will be difficult to obtain tolerance toward a MHC mismatched graft. After transplantation, in fact, both antigen presenting cells and T cells may represent potential targets of NK cell regulation
Activated NK cells can kill donor-derived dendritic cells through direct lysis, thus dampening the immune response and promoting a tolerogenic environment
Thanks Mohammed for your effort and hard work. I strongly advise you write in your own words.
Shereen Yousef
3 years ago
Natural killer (NK) cells are effector lymphocytes represent 5–10% of circulating lymphocytes.
NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect (1).
Thay are the main defence against viral infections and tumours.
NK cells produce cytokines like IFN-y, TNFa, and GMCSF which activate T cells, dendritic cells, macrophages, and neutrophils to enhance adaptive immune system
The NK cells perform their cytolytic effector activity through two main mechanisms of action (2) :
First Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
Second Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
inhibitory or stimulatory receptors on Nk cell surface determine the fate of the target cell
When signals from both receptors are equal as in normal self cells these cells are protected while neoplastic and infection cells induce the stimulation signals causing cell lysis(3) .
NK cells can be distinct into subsets characterized by different expression of cell surface proteins and cytokines
Natural killer type-1 (NK1) with activating signals, are mainly CD56dim CD11b+ CD27− cells produce IFN-g.
NK type-2 (NK2) , with inhibitory signals, are mainly CD56bright CD27− CD11b− and produce type-2 cytokines, including IL-5 and IL-13;
NK regulatory cells (NKreg with CD56brightCD27+ NK cells and play their immune regulatory effect by cytokines secretion or cell-to-cell contact (4).
NK cell in kidney disease :
NK cell present in high number in kidney biopsies from patients with chronic kidney disease both NK CD56dim and CD56bright cells were increased in fibrotic renal tissue, but only CD56bright correlated significantly with loss of kidney function (5),
NK cell role in kidney transplantation:
• Yagisawa et al. demonstrated, in a mice model of kidney transplantation, that acute kidney allograft rejection is induced by the presence of both NK cells and donor specific antibodies (DSA), whereas in the absence of NK cell activation the presence of DSA alone cannot induce acute antibody-mediated rejection, although it can still lead to late graft failure (6).
NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR (7)
CD56dim/CD16 NK cells the main NK subset involved .
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection .
• NK cells can increase maturation of dendritic cells resulting in activation of T cells (9).
•NK cells are source of IFN-g, which drive a Th1-type immune response.
•NK cells can interact directly with CD4+ T lymphocytes , increasing their reactivity, and these activities can induce acute rejection.
•acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis (10).
NK cells may also play a role in tolerance:
•Activated NK cells can kill donor dendritic cells through direct lysis , thus dampening the immune response and promoting a tolerance
•NK cells regulation could also affect recipient dendritic cells, thus influencing allograft antigen presentation (11).
•The maintenance of tolerance could be also associated with the production of IL-10 by NK cells which promote the development of regulatory dendritic cells .
NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .
It is therefore possible that NK cells per se do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response (8).
Immunosuppression Influence NK Cell Behavior?
Immunosuppressive drugs modulate the phenotype of NK cells after kidney transplantation, suggesting that NK cells can serve as sensors for immunosuppression and can be considered for personalized immunosuppression therapy adjustment(12) .
In fact, among kidney transplant recipients with a compared to healthy controls, patients receiving tacrolimus showed reduced expression of CD16 and CD56 on NK cells than patients treated with cyclosporine or tacrolimus in combination with mTOR inhibitors .
In addition, the presence of mTOR inhibitors in vitro also had functional consequences regarding de-granulation and IFN-g production (12)
In patients treated with cyclosporine compared to patients treated with tacrolimus, the number of NK cells as well as the ratio CD56dim/CD56bright is lower and the cytotoxic activity is reduced 1 year after transplantation .
Reference
1 Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57.
2 Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. (2016) 16:7–19.
3 Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol. (2006) 6:520–31.
4 Fu B, Tian Z, Wei H. Subsets of human natural killer cells and their regulatory effects. Immunology. (2014) 141:483–9.
5 Law BMP, Wilkinson R, Wang X, Kildey K, Lindner M, Rist MJ, et al. Interferon-γ production by tubulointerstitial human CD56(bright) natural killer cells contributes to renal fibrosis and chronic kidney disease progression. Kidney Int. (2017) 92:79–88.
6 Yagisawa T, Tanaka T, Miyairi S, Tanabe K, Dvorina N, Yokoyama WM, et al. In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection. Kidney Int. (2019) 95:350–62.
7 Yazdani S, Callemeyn J, Gazut S, Lerut E, de Loor H, Wevers M, et al. Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney Int. (2019) 95:188–98.
8 Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7.
9 Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM. Highlighting the role of DC-NK cell interplay in immunobiology and immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018).
10 . Dos Santos DC, Saraiva Camara NO, David DSR, Malheiros DMAC. Expression patterns of CD56+ and CD16+ cells in renal transplant biopsies with acute rejection: associations with microcirculation injuries and graft survival. Nephrology. (2017) 22:993–1001.
11 Hadad U, Martinez O, Krams SM. NK cells after transplantation: friend or foe. Immunol Res. (2014) 58:259–67.
12 Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, et al. The Peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs. Front Immunol. (2013) 4:46.
NK cells are cytotoxic cells, they do not require antigen exposure to mediate their effectnor complement to exert its damaging effect.
They accomplish their lytic effect through direct lysis and antibody dependent cellular cytotoxicity
NK cells can cause allograft injury,on the other hand NK cells may have a role in the priming of graft tolerance.
NK cells can contribiute to the pathogenesis of acute and chronic T cell-mediated and antibody-mediated rejection.
NK cells has an effect on maturation of dendritic cells and activation of T cells ,also NK cells produce IFN-g,that stimulate a Th1-type immune response and interact directly with CD4+ T lymphocytes leading to acute rejection.
NK role in antibody mediated rejection(ABMR) is started through expression of CD16,this is triggered by DSAs . NK cells was found in the peri-tubular capillaries of the biopsies of patients with ABMR.
NK cells may play also a role in the pathogenesis of T cell-mediated rejection.
A study demonstrated that biopsies from patients with T cell-mediated rejection showed an increased number of CD56bright NK cells while in the biopsies of those with antibody-mediated rejection both CD56bright and CD56dim NK cells were increased.
Kidney biopsies from ABMR patients revealed significant enrichment of NK cell transcripts, and activated NK cell infiltration can differentiate ABMR from TCMR and can indicate graft failure occurrence.
Suppression of NK-cell activity can improve the kidney graft survival
Mean while NK cells have potent immunoregulatory effects leading to tolerance induction by killing APCs
Tregs suppress NK cells and inhibit their effector functions
A direct correlation between NK cells and Tregs in inducing tolerance is controversial ,it is possible that there is a mutual antagonism between NK cells and Tregs.
NK cells can induce tolerance by blocking dendritic cells and T cells that could start rejection in the first 3 weeks after transplantation , while Tregs would maintain the long-term tolerance .
Reference
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L and Stallone G (2020) The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol. 11:1454
Natural killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5–10% of circulating lymphocytes. NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect.
NK cells may play also a role in the pathogenesis of T cell-mediated rejection. Immunohistochemical characterization of graft infiltrating cells demonstrated that patients with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, both characteristics of T cell-mediated rejection.
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
Yagisawa et al. recently demonstrated, in a mice model of kidney transplantation, that acute kidney allograft rejection is induced by the presence of both NK cells and donor-specific antibodies (DSA), whereas in the absence of NK cell activation the presence of DSA alone cannot induce acute antibody-mediated rejection, although it can still lead to late graft failure.
NK cells can also influence the maturation of dendritic cells and the subsequent activation of T cells. Moreover, NK cells are an early source of IFN-g, which drive a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes, increasing their reactivity, and these activities can induce acute rejection mechanisms.
Halloran PF. T cell-mediated rejection of kidney transplants: a personal viewpoint. Am J Transplant. (2010) 10:1126–34? DOI: 10.1111/j.1600-6143.2010.03053.x PubMed Abstract | CrossRef Full Text | Google Scholar
Yagisawa T, Tanaka T, Miyairi S, Tanabe K, Dvorina N, Yokoyama WM, et al. In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection. Kidney Int. (2019) 95:350–62. DOI: 10.1016/j.kint.2018.08.041 PubMed Abstract | CrossRef Full Text | Google Scholar
Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM. Highlighting the role of DC-NK cell interplay in immunobiology and immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018). DOI: 10.5772/intechopen.78804 CrossRef Full Text | Google Scholar
How do NK cells induce their effector actions on cells? How are they involved in ABMR? For example, at which compartment of glomerular histology should you look for NK cells activation?
How do NK cells induce their effector actions on cells?
NK cells mainly act by releasing Th1 type cytokines (Interferon Gamma, TNF, GMCSF) activating T cells, dendritic cells, macrophages and neutrophils. They also produce cytokines like CCL3, CCL4, CCL5 which are responsible for attraction of myeloid cells and effector lymphocytes towards the inflamed tissue.
How are they involved in ABMR? For example, at which compartment of glomerular histology should you look for NK cells activation?
In Antibody mediated rejection, NK cells act via CD16. DSA bound to graft endothelial cells interact with the CD16 on NK cell leading to antibody dependent cell mediated cytotoxicity against the graft. NK cells can be seen in the peritubular capillaries.
Reference: Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cell in the immune response in kidney transplantation. Front Immunol 2020;11:1454.
NK cells can have the effector function With the help of the CD16cytotoxic activity which is AB mediated in the presence of DSA antibody and lead to microvascular injury at the level of endothelial cells in ABMR and. Not necessarily to be complement mediated
Binding of DSA to the graft endothelium induces the expression of molecules attracting NK cells and other cells and expression of ligands that engage in NK cell activation receptors. Activation of NK cells through specific ligands and CD16 stimulate IFN-γ production and expression of other molecules that further enhance inflammation & mediating graft injury. In graft biopsy there will be microcirculation inflammation & tubulitis
References:
Miyairi S., Baldwin W.M., Valujskikh A., Fairchild R.L. Natural Killer Cells: Critical Effectors During Antibody-mediated Rejection of Solid Organ Allografts. Transplantation 2021;105: 284–290.
Yazdani S.,Callemeyn J., Gazut S., Lerut E., et al. Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney International(2019)95,188–198.
NK cells exert their cytolytic effector action through
Direct lysis: NK cells have inhibitory receptors that recognize self HLA class I molecules and inhibit its cytotoxicity activity. In absence of self HLA class I molecules on target cells stimulate cytotoxicity of NK cells.
Antibody dependent cellular cytotoxicity: induce cell lysis through interaction between Fc receptor on NK cells and Fc fragment of an antibody recognizing foreign antigens on those target cells
The lytic function depend on cytolytic molecules granzymes and perforins which lead to production of several inflammatory cytokines.
NK cells were identified in biopsies of antibody mediated rejection in the peritubular capillaries where DSA bind the graft endothelial cells
Morvan MG, Lanier LL. NK cells and cancer: you can teach innate
cells new tricks. Nat Rev Cancer. (2016) 16:7–19
Paul S, Lal G. The molecular mechanism of natural killer cells function
and its importance in cancer immunotherapy. Front Immunol. (2017)
8:1124.
Yazdani S, Callemeyn J, Gazut S, Lerut E, de Loor H, Wevers M, et al. Natural
killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney Int. (2019) 95:188–
98.
Excellent response and it is to the point. You need to improve the style and structure of your writing.
saja Mohammed
3 years ago
Natural killer (NK) cells are effector lymphocytes originated from common lymphoid progenitors and represent 5–10% of circulating lymphocytes.NK cells represent one of the main cellular components of innate immunity
NK cells are different from cytotoxic T cells so they dont not require antigen exposure to mediate their effect , they are named for this natural killing cells .
They mediate immune responses against intracellular pathogens, soNK cells mainly produce cytokines including IFN-y, TNFa, and GMCSF which facilitate the activation of T cells, dendritic cells, macrophages, and neutrophils to enhance adaptive immune system
NK cell receptor repertoire is highly complex in human. And can express specific stimulatory and inhibitory receptors for various other ligands present on the surface of the target cells and the balance of inhibitory and stimulatory signals received by a NK cell determines the outcome of its interactions with target cells.
Normal cells are protected from NK cell killing since stimulatory receptors signals are balanced by inhibitory receptors signals coming from the interaction with the self-molecules of the MHC class I complex.
Mechanism of activation include
1-Direct lysis
2-Antibody-dependent cellular cytotoxicity (ADCC).
another essential feature of NK cell, is the production of pro-inflammatory or immunosuppressive cytokines .and the APC like dendritic cells can enforce the Cytolytic activity of the of NKC through the production of critical cytokines such as IL15, 12, 23, 27, and 18.
Recent studies in human found that subsets of NKC like NK CD56dim and CD56bright cells were increased in fibrotic renal tissue, but only CD56bright correlated significantly with loss of kidney function through the production of pro-inflammatory cytokines and IFN-g, that can play an important role in fibrotic process and in the progression of kidney injury.
NK Cell Involvement in Acute and Chronic Allograft Rejection
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.NK cells can also influence maturation of the APC like dendritic cells and lead to subsequent activation of T cells, Immunohistochemical characterization of graft infiltrating of CD56+ and CD57+ cells expression within the interstitial compartment, associated with interstitial inflammation and tubulitis which characterized the acute cellular rejection. NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR, where DSA bind the graft endothelial cells. DSA can interact with FcγRIII present on NK cells inducing an ADCC against the graft lead to endothelial cell injury.NK cells have been identified in the peri-tubular
Transplant tolerance.
Activated NK cells can directly kill donor-derived dendritic cells, thus promoting transplant tolerance. In mice tolerant models, NK cells can also produce high levels of IL10 thus showing tolerogenic ability. Both NK cells and Tregs might also influence each other by a mutual antagonism or by a temporary definition of their contribution in the induction of transplant tolerance.
Immunosuppressive drugs might modulate the phenotype of NK cells that can keep their ability to respond to stimulation. Moreover, immunosuppression can reduce the number of NK cells after transplantation, so Monitoring NK cell numbers and functions in transplanted patients under specific immunosuppressive regiments is important predict the onset of infections and neoplasia. they are considered as attractive target for cancer immunotherapy becuase of thier ablity to kill tumour cells . REFERNCES: 1-Halloran PF. T cell-mediated rejection of kidney transplants: a personal viewpoint. Am J Transplant. (2010) 10:1126–34. doi: 10.1111/j.1600-6143.2010.03053. 2- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24. doi: 10.4049/jimmunol.173.6.3716 PubMed Abstract | CrossRef Full Text | Google Scholar 3- 59. Dos Santos DC, Saraiva Camara NO, David DSR, Malheiros DMAC. Expression patterns of CD56+ and CD16+ cells in renal transplant biopsies with acute rejection: associations with microcirculation injuries and graft survival. Nephrology. (2017) 22:993–1001. doi: 10.1111/nep.12897 PubMed Abstract | CrossRef Full Text | Google Scholar. 4The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation -Front. Immunol., 23 July 2020 | https://doi.org/10.3389/fimmu.2020.01454
Thank you Dr. Saja Excellent response You raised the bar for all other candidates
Professor Ahmed Halawa
Admin
3 years ago
Dear All Does NK cells needs stimulation by antigen? Does NK cells needs complement to exert its damaging effect? If it is involved in Acute Antibody Mediated Rejection, do expect C4d staining to be positive?
NK cells dose not need antigen to stimulate their effect , thats why called natural killers they are different from cytoxic T cells as the later need priming by APCs they act by direct lysis effect and antibody dependent cell cytoxtoxicity ADCC .
the do involved in both ACR and ABMR
NK cells are natural cytotoxic cells. They do not require any antigen exposure. Complement is not involved in their mechanism for graft rejection, hence C4d staining would be negative
NK cells does not need stimulation by antigen to exert their effect, also no complement activation is needed, it involves in both ABMR and T cell mediated rejection pathology ,, C4d is negative as there is no complement involvement
1-No they doesn’t stimulate by antigen
2-Yes they use complementary receptors
3-yes as the complement pathway is involved in their activation I expect the C4d will be positive
NK cells are a part of natural immunity. Deficiency or absence of MHC-class I may lead to activation of NK calls so there is no need to antigen for stimulation, and after activation, NK cells kill their target cells by secreting granzyme, perforin and INFγ and differentiate to memory cells. They don’t need to complement for activation and therefore C4d staining will not be positive after acute rejection.
Esmat MD
3 years ago
NK cells along with macrophages, neutrophils, cytokines, certain cellular receptors, and complement system are part of natural or innate immunity and belong to the family of innate lymphoid cells (ILCs).
Human NK cells normally constitute 5-15% of human peripheral blood lymphocytes.
NK cells are lymphoid cells with unique features that do not carry BCRs and TCRs but express activating and inhibitory receptors including TLR2, 3, 4, 5, 7, and 8, and respond to the respective TLR ligands directly. Activating receptors play role in infection and inflammatory states by recognition of ligands on different cell types while inhibitory receptors bind self MHC class I molecules.
Stimulation of NK cells occurs once balance is in favor of activating signals. Indeed, the inhibitory receptors on NK cells are counterbalanced by activating receptors that recognize stress ligands expressed on the cell surface in response to intracellular DNA damage. NK cells distinguish and avoid healthy host cells through receptors that recognize MHC class I molecules expressed on all normal healthy cells. Binding of these receptors inhibits NK cell-mediated lysis, whereas deficiency or absence of MHC I leads to activation of the process of target attack and cell lysis.
Since allograft tissue expresses non-self MHC molecules, they do not engage inhibitory receptors on donor NK cells and so lead to NK cells activation. Thus, NK cells interestingly respond to missing self. On the other hand, NK cells infiltrating in to allograft can be activated by binding of alloantibodies in the graft to FcRs on NK cells. Once activated, NK cells kill their target cells by secreting granzyme, perforin and INFγ and differentiate to memory cells.
Another role of NK cells in allograft rejection is in the context of viral infections (especially herpes virus infections) that infected cells, because of diminished expression of MHC-class I and increased expression of activating ligands, are rapidly detected by NK cells and are killed.
(Traditionally, NK cells are considered cells of the innate immune response; however, there is accumulating evidence that at least some subsets respond to certain antigens in a manner that has the hallmarks of adaptive immunity.
The first evidence of this came from observations that mice deficient in T cells and B cells acquire antigen-specific immunological memory to hapten-based contact sensitizers that is mediated by a subset of primed, hepatic NK cells. Subsequent work has demonstrated that NK cells also acquire long-lived memory of diverse viral antigens.)
Paust S, von Andrian UH. Natural killer cell memory. Nat Immunol 2011 Nikzad R, Angelo LS, Aviles-Padilla K, et al. Human natural killer cells mediate adaptive immunity to viral antigens. Sci Immunol 2019
(In recent years, it has been appreciated how infection with human cytomegalovirus (HCMV) can shape the NK cell receptor repertoire. This HCMV-induced NK cell subset, interacting with self-HLA class I molecules. In addition, these NK cells can display some hallmarks of adaptive immunity, such as, enhanced effector function, longevity, clonal expansion as well as given epigenetic modifications, including epigenetic remodeling at the IFNG locus, and decreased expression of certain signaling molecules such as the adaptor protein FcRγ. HCMV infection also contributes to age associated changes in NK cells.
Similar to HCMV infection, Epstein-Barr virus (EBV) infection may change the composition of NK cells.
Natural killer cells may display alloreactive potential in case of mismatch between recipient inhibitory KIRs and graft HLA class I molecules in the context of solid organ transplantation including kidney transplantation. In this context, several lines of evidence support that “adaptive” NK cells may contribute to control viral infection in kidney transplant recipients. On the other hand, increasing evidence supports that alloantibody-mediated NK cell activation via Fc.RIIIA (CD16) may contribute to rejection in kidney transplant recipients.
Importantly, in addition to NK cells, ILCs may also represent important players in the early phases after transplantation.)
Marcenaro E, Notarangelo LD, Orange JS, Vivier E. Editorial: NK Cell Subsets in Health and Disease: New Developments. Front Immunol 2017
Alyaa Ali
3 years ago
Natural killer cells are effector lymphocyte and they represent 5% to 10% of circulating lymphocytes
they are one of the main cellular component of the innate immunity , they are natural cytotoxic , they play a role against intracellular pathogens as well as they have a role in many inflammatory diseases through production of cytokines.
mechanism of their action by direct lysis or antibody dependent cellular cytotoxicity
( ADCC) Natural killer cells in transplantation
NK cells have a role in acute and chronic T cell mediated rejection / antibody mediated rejection
Antibody mediated rejection through the expression of CD16. This function can be triggered by anti-HLA antibodies, in particular by DSAs . where DSA bind the graft endothelial cells. Once bound to endothelial cells DSA can interact with FcγRIII present on NK cells inducing an ADCC against the graft.. NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR.
T cell mediated rejection through the secretion of pro-inflammatory molecules such as IFN-g , which increase the recruitment of alloreactive T cells and up-regulate HLA alloantigens (MHC I and II) on graft target cells, making them more susceptible to cytotoxic killing .patients with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, both characteristics of T cell-mediated rejection. NK Cells and Transplant Tolerance
Natural killer cell can cause tolerance after their activation by inflammatory environment mediated by the cytokines produced by dendritic cells and T cells . These activated NK cells can kill donor-derived dendritic cells through direct lysis , thus inhibiting the immune response and promoting induction of tolerance . NK cells and immunosuppressive drugs
Immunosuppressive drugs have limited effect on the activity of NK cells in transplant recipients .
From a therapeutic point of view, and new treatments targeted to activated NK cells and/or their effector functions should be explored.
Immunosuppression may influence the number of NK cells over time. In patients treated with cyclosporine compared to patients treated with tacrolimus.
Routine monitoring NK cell number in the context of immunosuppressive regimens
in transplanted patients is important to control and predict the onset of infections and neoplasia . NK cells, indeed, play an important role in cancer defense, and the incidence of cancer is deeply increased after transplantation and playing important role in protecting against human Cytomegalovirus infection. References
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol. 2020;11:1454.
NK cells represent are one of the main cellular components of innate immunity(5–10% of circulating lymphocytes).
§ They are named “natural killers” because they do not require activation to kill cells that are missing “self” markers of MHC class I. NK cells can be identified by the presence of CD56 and the absence of CD3
§ Theses cytotoxic cells are analogous to the cytotoxic T cells in the adaptive immune system . However, they do not require antigen exposure to mediate their effect.
§ The interaction of NK cells with target cell to define their fate is determined by a balance between stimulatory and inhibitory receptors. Inhibitory receptors (KIR) recognize cognate MHC I, and this ‘switches off’ NK cell, preventing it from killing.
NK Subsets: NK cells can be classified as CD56bright or CD56dim.CD56bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines, whereas, CD56dim NK cells are always CD16 positive(key for ADCC)
Function of NK cells:
1. The NK cells has a cytolytic effector activity through the production of proteins as perforin and proteases called granzyme
2. Antibody-dependent cell-mediated cytotoxicity (ADCC):Antibodies that bind to antigens can be recognized by CD16 receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis
.
3. NK cells secrete interferon gamma and Tumor necrosis factor alpha .IFNγ activates macrophages for phagocytosis and lysis and TNFα acts to promote direct NK tumor cell killing and controlling viral infections(1).
NK cells in Renal transplantation:
NK cells promote allograft injury but also play a role in the priming of allograft tolerance
Role of NK cells in Acute and Chronic Allograft Rejection:
· NK cells can influence maturation of dendritic cells and the subsequent activation of T cells.
· NK cells are an early source of IFN-g, which drive a Th1-type immune response.
· NK cells can interact directly with CD4+ T lymphocytes ;increasing their reactivity, and induce acute rejection mechanisms.
· NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
· Turner et al (2) found that in antibody-mediated rejection, NK cells is demonstrated in the transplant renal biopsy (peri-tubular capillaries) whereas T cell-mediated rejection was confirmed by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis. (3).
· Data signifies the importance of CD56dim cells activation in featuring ABMR, where they can guide vascular damage but CD56bright NK cells can instead play a specific role in TCMR(4).
· The different role of NK cells in ABMR compared to the TCMRwas studied kidney graft biopsies that revealed high levels of NK cells in early T cell-mediated rejection while late biopsies showed increased number of NK cell in patients with antibody-mediated rejection, microvascular inflammation, and DSA(5).
The role of NK Cells in Transplant Tolerance:
The direct correlation between NK cells and Tregs in inducing tolerance is currently controversial It is thought NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .It is therefore possible that NK cells do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response(6).
The effect of immunosuppression on NK cells:
· Immunosuppressive drugs can modulate the phenotype of NK cells following renal transplantation, so, NK cells can act as sensors for immunosuppression .
· Current immunosuppressive regimens are unable to down-regulate the function of NK cells and thus new treatments targeted to activated NK cells should be explored. (1).
References:
1)The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Paola Pontrelli et al,. Front. Immunol., 23 July 2020
2) Natural killer cells in kidney health and disease Turner JE, Rickassel C, Healy H, Kassianos AJ. Front Immunol. (2019)
3) Compartment-specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection. Dos Santos DC, Campos EF, Saraiva Câmara NO, David DS, Malheiros DM. Transpl Int. (2016) 29:443–52
4) Specialized roles of human natural killer cell subsets in kidney transplant rejection. Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Front Immunol. (2019)
5) Interpreting F NK cell transcripts versus T cell transcripts in renal transplant biopsies. Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran P. Am J Transplant. (2012) 12:1180–91
6)The varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. Beilke JN, Grill RG. Frontiers in nephrology: J Am Soc Nephrol. (2007)
§ NK cells represent are one of the main cellular components of innate immunity(5–10% of circulating lymphocytes).
§ They are named “natural killers” because they do not require activation to kill cells that are missing “self” markers of MHC class I. NK cells can be identified by the presence of CD56 and the absence of CD3
§ Theses cytotoxic cells are analogous to the cytotoxic T cells in the adaptive immune response. However, they do not require antigen exposure to mediate their effect.
§ The interaction of NK cells with target cell to define their fate is determined by a balance between stimulatory and inhibitory receptors. Inhibitory receptors (KIR) recognize cognate MHC I, and this ‘switches off’ NK cell, preventing it from killing.
NK Subsets: NK cells can be classified as CD56bright or CD56dim.CD56bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines, whereas, CD56dim NK cells are always CD16 positive(key for ADCC)
Function of NK cells:
1. The NK cells has a cytolytic effector activity through the production of proteins as perforin and proteases called granzyme
2. Antibody-dependent cell-mediated cytotoxicity (ADCC):Antibodies that bind to antigens can be recognized by CD16 receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis.
3. NK cells secrete IFNγ and TNFα.IFNγ activates macrophages for phagocytosis and lysis and TNFα acts to promote direct NK tumor cell killing and controlling viral infections(1).
NK cells in Renal transplantation:
NK cells promote allograft injury but also play a role in the priming of allograft tolerance
Role of NK cells in Acute and Chronic Allograft Rejection:
· NK cells can influence maturation of dendritic cells and the subsequent activation of T cells.
· NK cells are an early source of IFN-g, which drive a Th1-type immune response.
· NK cells can interact directly with CD4+ T lymphocytes ;increasing their reactivity, and induce acute rejection mechanisms.
· NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
· Turner et al (2) found that in antibody-mediated rejection, NK cells is demonstrated in the transplant renal biopsy (peri-tubular capillaries) whereas T cell-mediated rejection was confirmed by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis. (3).
· Data signifies the importance of CD56dim cells activation in featuring ABMR, where they can guide vascular damage but CD56bright NK cells can instead play a specific role in TCMR(4).
· The different role of NK cells in ABMR compared to the TCMRwas studied kidney graft biopsies that revealed high levels of NK cells in early T cell-mediated rejection while late biopsies showed increased number of NK cell in patients with antibody-mediated rejection, microvascular inflammation, and DSA(5).
The role of NK Cells in Transplant Tolerance:
The direct correlation between NK cells and Tregs in inducing tolerance is currently controversial It is thought NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .It is therefore possible that NK cells do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response(6).
The effect of immunosuppression on NK cells:
· Immunosuppressive drugs can modulate the phenotype of NK cells following renal transplantation, so, NK cells can act as sensors for immunosuppression .
· Current immunosuppressive regimens are unable to down-regulate the function of NK cells and thus new treatments targeted to activated NK cells should be explored. (1).
2) Natural killer cells in kidney health and disease Turner JE, Rickassel C, Healy H, Kassianos AJ. Front Immunol. (2019)
3) Compartment-specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection. Dos Santos DC, Campos EF, Saraiva Câmara NO, David DS, Malheiros DM. Transpl Int. (2016) 29:443–52
4) Specialized roles of human natural killer cell subsets in kidney transplant rejection. Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Front Immunol. (2019)
5) Interpreting F NK cell transcripts versus T cell transcripts in renal transplant biopsies. Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran P. Am J Transplant. (2012) 12:1180–91
6)The varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. Beilke JN, Grill RG. Frontiers in nephrology: J Am Soc Nephrol. (2007)
Natural Killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5-10% of circulating lymphocytes and have a different subset. They are natural cytotoxic cells, but unlike cytotoxic T lymphocytes, they don’t require antigen exposure to mediate their effect. They achieve their cytolytic effector activity through 2 main mechanisms of action:
1. Direct lysis
2. Antibody-dependent cellular cytotoxicity(ADCC)
-In both mechanisms, the lytic function of NK cells depends upon cytolytic molecules, mainly granzyme and perforin, and their activation leads to the production of several inflammatory cytokines.
-NK cells link between innate and adaptive immune systems and protect against excessive immune response to antigens.
– NK influence the maturation of dendritic cells and subsequent activation of T cell also NK can interact directly with CD4 T lymphocytes, increasing their reactivity and can induce acute rejection.
-NK cells are involved in different ways in acute and chronic T-cell mediated rejection and antibody-mediated rejection.
-CD56dim/CD16 NK cells represent the main NK subset involved in the pathogenesis of ABR by ADCC on the target cell into the graft.
-NK cells can kill donor-derived dendritic cells through direct lysis that leads to promote tolerance that can be maintained with the production of IL-10 by NK cells.
-Immunosuppressive drugs might modulate the phenotype of NK cells after kidney transplantation and influence the number of NK over time.
-Monitoring NK cells number in the transplanted patient can predict the onset of infection and neoplasia. Referrence:
Paola Pontrelli, Federica Rascio, Giuseppe Castellano, Giuseppe Grandaliano, Loreto Gesualdoand Giovanni Stallone. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol., 23 July 2020
1. NK cells are cytotoxic lymphocytes that are secreted from bone marrow
2. Located mainly in the peripheral circulation with minority in organs
3. Constitutes 5-10% of total lymphocytes in peripheral blood
4. Responsible for innate and not adaptive immunity
5. Do not have antigen specific receptors like TCR for T cells and IG for B cells but have activating and inhibitory cell surface receptors (1)
Activation and inhibition of NK cells
⦁ Inhibited by binding of inhibitory cell surface receptors (one of them is KIRs) to MHC antigens class I which is present on the surface of the host healthy cells (1)
⦁ Activated by recognizing damaged cells (infected or malignant cells ) with no MHC class I antigens on its surface since these cells downregulate MHC class I molecules
⦁ So damaged cells are killed while healthy cells are avoided
⦁ NK cell become attached to the target cell either by direct interaction between ligands on target cells and conjugate receptors on NK cells without the need for adaptive immune response (spontaneous cytotoxicity) or through attachment to Fc portion of IgG attached to target cell (antibody-dependent cellular cytotoxicity)
Effect of activated NK cells
⦁ Cytotoxic killing of target cell occur by secreting granules that disrupt target cell membrane and induce apoptosis (2).
⦁ NK cells increase the activity of CD4+ T lymphocytes through direct interaction (3).
⦁ NK1 cells secrete interferon (IFN)-gamma that activates macrophages, and stimulate CD4 T helper 1.
⦁ NK2 cells produce IL-5 and IL-13 that induce humoral immunity and may play a rule in bronchial asthma and atopic diseases.
⦁ NK cells produce IL 10 that lead to development of regulatory dendritic cells leading to tolerance (4)
Clinical significance of NK cells in renal transplantation
1. Play an important rule in acute and chronic TCMR, ABMR (5) through either antibody- dependent cellular cytotoxicity , activation of CD4 T helper 1 response, promotion of migration of immune cells to the graft especially dendritic cells or through direct infiltration of the graft by NK cells.
2. Play an important rule in clinical tolerance
3. Immunosuppression decrease NK cells function and number leading to increase in the incidence of malignancy and infection.
4. Immunosenecence reported in elderly population occur in part due to decrease in number and function of NK cells (6)
REFERANCES
1- Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235:286
2- Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2:735.
3- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
4- Jiang X, Kojo S, Harada M, Ohkohchi N, Taniguchi M, Seino KI. Mechanism of NKTcell-mediated transplant tolerance. Am J Transplant. (2007) 7:1482–90.
5- Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7
6- Tobin LM, Mavinkurve M, Carolan E, et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2017; 2.
NK cells are natural cytotoxic cells, but don’t need antigen exposure to mediate immune response ( unlike cytotoxic T cells). It comprises 5-10% of total circulating lymphocytes. It considered as one of innate immunity component. Its immune response usually against intracellular pathogens but also had another role through production of different cytokines. Nk cells accomplish cytolytic activity through:
direct lysis : inhibitory receptors on NK surface can recognize HLA class I molecules.
Abs- dependent cellular cytotoxicity: interaction between CD16 on NK cells & Abs recognizing foreign antigen on target cells lead to lysis of the cells.
Another feature of NK cells is production of pro inflammatory & immunosuppressive cytokines which is different from cytotoxic granules secretion.
NK cells is the main regulator of immune response & it cross-talk between innate & adaptive immunity. Nk cells activated by various soluble factors ( IL5, type I INF, IL12, IL18) so it can induce maturation & stimulation of dendritic cells, macrophages & T cells
Nk cells role in solid organ transplant still controversial , but it may promot graft injury. There is some evidence that NK cells may play major role in priming graft tolerance. Also it found that the number & phenotypes of NK cells are different in post transplant than in pre transplant, so it may play a role in graft out come.
NK cells can directly interact with CD4 T cells & increase their activity so increase the risk of acute rejection. Yagisawa et al found that in mice renal transplant the acute rejection is caused by presence of both NK cells & DSA, & in absence of NK cells activation & presence of DSA alone can not induce acute AMR, but it still lead to late graft failure. NK cells have a role in T cell mediated rejection.
Reference:
Pontrelli P., Rascio F., Castellano G., et al. The Role of Natural Killers in the Immune Response in Kidney Transplantation. Front Immune, 2020.
Yes, NK cells are natural cytotoxic cells, but don’t need antigen exposure to mediate immune response (unlike cytotoxic T cells) and also do nor require complement to exert its damaging effect.
Well done
Mohamad Habli
3 years ago
Natural killer cells is a population of lymphocytes that represent one of the main cellular components of innate immunity along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. NK represent 5–10% of circulating lymphocytes. In addition to their role in anti-viral and anti-tumor defense, they have impact in alloimmune response in kidney transplant. NK cells lack TCR or BCR but they have complementary activating and inhibiting receptors. Growing evidence is suggesting a major role of NK cells in the pathogenesis of immune-mediated allograft damage. Specific NK cell subsets are associated with tolerance in kidney transplant recipients. On the other side, activated NK cells are associated with chronic AMR and graft loss.
The NK cells accomplish their cytolytic effector activity through two main mechanisms of action:
1. Direct lysis of graft cell. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self ” instead, the absence of class I HLA molecules on target cells prevents inhibitory signals and leading to of secreting same molecules as the cytotoxic T lymphocytes and subsequent killing/lysing the target cell.
2. Antibody-dependent cellular cytotoxicity. The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells induces the lysis of these cells.
3- T NK cells are also implicated in IFN-g release, which drives a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes, increasing their activity in inducing ABMR.
4- NK cells can also influence maturation of dendritic cells into APC and the subsequent activation of cells. Immuno-histochemical staining of kidney graft with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, that are characteristics of T cell-mediated rejection.
5-NK cells have potent immunoregulatory properties that influence tolerance induction. The maintenance of transplant tolerance could be also associated with the production of IL-10 by NK cells. Upon stimulation with glycolipids, NK cells produce high levels of IL-10 that can promote the development of regulatory dendritic cells.
Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells, coming from a common progenitor. However, NK cells are classified as group I Innate Lymphocytes (ILCs) and respond quickly to a wide variety of pathological challenges. NK cells are best known for killing virally infected cells and detecting and controlling early signs of cancer. Role of NK Cells in Kidney Transplantation
NK cells have a key role in the pathogenesis of immune-mediated graft damage in kidney transplantation.
1-Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. 2-On the other side, alloreactive NK cells are associated with chronic antibody-mediated rejection and graft loss.
3-In addition, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased alloimmune response and, eventually, to chronic graft rejection.
4- Activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Immunosuppression effects on NK Cell Behaviour
Immunosuppressive drugs might modulate the phenotype of NK cells after kidney transplantation, thus suggesting that NK cells can serve as sensors for immunosuppression and can be considered for personalized immunosuppression therapy adjustment.
immunosuppression may influence the number of NK cells over time. In patients treated with cyclosporine compared to patients treated with tacrolimus, the number of NK cells as well as the ratio CD56dim/CD56bright is lower and the cytotoxic activity is reduced 1 year after transplantation.
It will be useful in the future to routinely monitor and evaluate NK cell function in the context of specific algorithms to personalize immunosuppressive regimens.
Moreover, Monitoring NK cell number and especially NK cell function in transplanted patients is also important to control and predict the onset of infections and neoplasia. References 98. Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, et al. The Peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs. Front Immunol. (2013) 4:46. doi: 10.3389/fimmu.2013.00046 99. Vacher-Coponat H, Brunet C, Moal V, Loundou A, Bonnet E, Lyonnet L, et al. Tacrolimus/mycophenolate mofetil improved natural killer lymphocyte reconstitution one year after kidney transplant by reference to cyclosporine/azathioprine. Transplantation. (2006) 82:558–66. doi: 10.1097/01.tp.0000229390.01369.4a 100. Stallone G, Infante B, Grandaliano G. Management and prevention of post-transplant malignancies in kidney transplant recipients. Clin Kidney J. (2015) 8:637–44. doi: 10.1093/ckj/sfv054
NK cells are effector lymphocytes derived from common lymphoid progenitors and represent 5-10% of circulating lymphocytes. They are natural cytotoxic( do not require antigen exposure to exert their effect).
The role of NK cells in transplantation:
influence maturation of dendritic cells and the subsequent maturation of T cells
NK cells are an early source of IFN-g which derive a Th1 type immune response.
interact directly with CD4+ T lymphocytes increasing their activity and leading to rejection
NK CD56dim/CD16 represent the main subset involved in ABMR.
NK cells play a role in the pathogenesis of T cell mediated rejection ( CD56+/ CD57+).
NK Cells have potent immunoregulatory function that promote transplant tolerance.
immunosuppressive medications can modulate the type of NK cells after transplantation, thus NK cells can serve as sensor for immunosuppression and can be considered for personalized immunosuppression therapy adjustment.
NK cells represent an immunological barrier in xenotransplantation.
References:
Pontrelli P., Rascio F., Castellano G.,Grandaliano G., et al. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 2020. Jul.Vol. 11, article 1454.
Resch Th., Fabritius C., Ebner S., Ritschl P., et al. The Role of Natural Killer Cells in Humoral Rejection. Transplantation 2015;99: 1335–1340.
Natural Killer cells role in transplantation:
1- Regarding acute rejection: upon stimulations, NK cells secrete different cytokines e.g. IFN gamma which in some studies was found to cause arterial stenosis with resultants graft rejection/(1) In addition, IFN gamma may lead to activation of T cells as well.
2- NK can recognize certain ligands which upon activation may lead to graft rejection.
3- on the other hand, NK cells may help in tolerance of transplanted organ as NK help in elimination of donor dendric cells so they helped in prevention of activation of T cells and rejection process (2)
4 – the exact mechanism of NK cells role in transplantation is still not clearly under stood. also, there is no coloration between NK cells activation and rejection.(3)
References:
Uehara S, Chase CM, Kitchens WH et al. NK cells can trigger allograft vasculopathy: The role of hybrid resistance in solid organ allografts. J Immunol 2005; 175: 3424–3430.
Multiple roles of NK cells in kidney transplantation:
1- NK cells that present CD56/CD16 can interact with DSA present on graft endothelial cells and induce antibody mediated rejection.
2- Also has a role in cellular rejection by release of interferon gamma (pro inflammatory mediator) from NK CD56.
3- Transplant tolerance, it has a positive role in transplant tolerance as it kills dendritc cells of donor (APC), also can release IL-10 which possess tolerogenic character, also antagonistic effect between Treg and NK cells is evident to induce tolerance.
4- Immunosuppressive drugs like CNI and mTor inhibitors can modify its function and decrease its number.
5- Still NK cells have anti infectious and anti-tumor function.
Paola Pontrelli, Federica Rascio, Giuseppe Castellano, Giuseppe Grandaliano, Loreto Gesualdo. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 23 July 2020.
Natural killer (NK) cells are effector lymphocytes that develop from common lymphoid progenitors, accounting for 5–10% of all circulating lymphocytes. NK cells are natural cytotoxic cells that do not require antigen exposure to exert their effect, unlike cytotoxic T lymphocytes.
Along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells, NK cells are one of the most important biological components of innate immunity.
They exert immune responses against intracellular pathogens.
The NK cells accomplish their cytolytic effector activity by:
1. Direct lysis. The recognition of HLA class I molecules by inhibitory receptors on NK cells inhibits their cytotoxic activity. Thus, rather than the presence it’s the absence of class I HLA molecules on target cells leads to the cytotoxicity of NK cells.
2. Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
The multiple role of NK cells in kidney transplantation.
(A) Graft rejection=
CD56dim/CD16 NK cells can promote ADCC against the graft by interacting with DSA bound to the graft endothelial cells, thus driving antibody-mediated rejection (ABMR). CD56bright NK cells can instead play a specific role in cell-mediated rejection (TCMR) through the secretion of pro-inflammatory molecules such as IFN-g.
(B) Transplant tolerance=
activated NK cells can directly kill donor-derived dendritic cells, thus promoting transplant tolerance. NK cells can also produce high levels of IL10 thus showing tolerogenic ability. NK cells and T regs might also influence each other by a mutual antagonism or by a temporary definition of their contribution in the induction of transplant tolerance.
(C) Immunosuppression=
Immunosuppressive drugs might modulate the phenotype of NK cells that can retain their ability to respond to stimulation. Moreover, immunosuppression can reduce the number of NK cells after kidney transplantation.
The Role of Natural Killer Cells in the Immune Response in Kidney TransplantationPaola Pontrelli et al
Natural killer cells are involved in allo immune reaction. Specific NK cells subsets are related to tolerance while others are related to chronic AB mediated rejection and graft loss.
Cytolytic effector activity of NK cells are produced through direct lysis and AB dependent cellular toxicity.
NK cells have antiviral and antitumor effects
increased post Tx incidence of malignancy and infection could be explained by effect of immunosuppression on NK cells.
References:
Pontrelli, P et al : The role of natural killer cells in the immune response in kidney transplantation, Front. Immunol ,2020,11:1454
natural killer sub type of T lymphocyte that can attack foreign AG as apart of cellular immunity and it also can lyse AG-AB complex (no need for APC to be activated)
its role in graft rejection mostly cellular rejection as it not need APC to recognize graft so it has a rapid action if no good induction to deplete it , it also help in humoral rejection as it secret inflamatory cytokines
Natural killer cells are considered a subtype of lymphocytes but are part of innate immunity
They represent around 5-10% of peripheral circulating lymphocytes
They carry stimulatory signals and inhibitory signals that bind to cells by multiple ligands and the net balance decided its action thus antigen on APC isn’t needed for activation.
NK cells stimulation elicit it’s action through 3 main ways:
*Direct cell lysis: switch into cytotoxic NKCs and cause destruction of cell membrane.
*Complement dependent cytotoxicity
*Secretion of Inflammatory cytokines causing macrophages and dendritic cells migration and naïve T-cell maturation into Th1 which leads to adaptive immunity involvement.
They play an important role in graft rejection and tolerance
* NK switching to cytotoxic NK cause graft destruction, more exposure of alloantigen ,involvement of adaptive immunity both cellular and humoral eventually causing ABMR.
*NKCs attack donor derived APC post-transplant and inhibit direct pathway stimulation of immunity which usually associated with acute rejection post-transplant also NKreg secrets IL-10 which elicit inhibitory effect on adaptive immunity.
Natural Killer Cells
Another participant in the alloimmune response is the NK cell. NK cells are lymphoid cells that do not carry TCRs or
BCRs but instead express complementary activating and inhibitory receptors. Activating receptors recognize ligands
induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class I
molecules. NK cells are stimulated when the balance between activating and inhibitory signals is tilted in favor of the
former. Since allograft tissues express nonself MHC proteins, they do not engage inhibitory receptors on donor NK,
leading to NK-cell activation. Therefore, in contrast to alloreactive T and B lymphocytes which respond to nonself,
NK cells respond to missing self. NK cells that infiltrate allografts can also be activated by binding of alloantibodies
in the graft to FcRs on NK cells. Once activated, NK cells kill their targets by secreting the same molecules utilized
by CTL (perforin, granzyme, and IFNy) and differentiate to memory cells. Despite their cytotoxic and memory
functions, NK cells appear to have a secondary role in allograft rejection. Their most conspicuous role in immunity is
in the setting of viral infection. Infected cells are rapidly detected by NK cells because of diminished MHC class I
expression and increased expression of activating ligands.
GABRIEL M. DANOVICH ,HANDBOOK OF KIDNEY TRANSPLANTATION ,
Natural killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5–10% of circulating lymphocytes. NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect .NK cells represent one of the main cellular components of innate immunity along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. They mediate immune responses against intracellular pathogens representing key mediators of the anti-viral and anti-neoplastic defense, but they also play a key role, through the production and release of several cytokines, in many inflammatory diseases, including acute and chronic kidney diseases.Interestingly, the role of this lymphocyte subset in the progression of kidney injury is starting to be uncovered .
The NK cells accomplish their cytolytic effector activity through
two main mechanisms of action :
*Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
*Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
In both cases, the lytic function of NK cells depends upon cytolytic molecules, mainly granzyme and perforin, and their activation leads to the production of several inflammatory cytokines . Granzyme and perforin are included into cytoplasmic lytic granules, characterized by several lysosomal-associated membrane glycoproteins (LAMPs) into the lipid bilayer. These proteins appear on cell surface after cytotoxic granules exocytosis . Among the different LAMPs, CD107a/LAMP-1 has been widely used as a functional marker to identify NK cell activity, since its expression is significantly higher on the surface of NK cells after MHC stimulation and correlates with both cytokine secretion and NK cell-mediated lysis of target cells .Interestingly, Conehn et al. demonstrated that CD107a/LAMP-1 protects NK cells from self-destruction upon target cell killing, since CD107a/LAMP-1 deficiency, both in human and in mice NK cells, increased NK cell apoptosis after degranulation .
The interaction of NK cells with the target cell can occur through distinct inhibitory or stimulatory receptors and, therefore, defines the fate of the target cell . Normal cells are protected from NK cell killing since stimulatory receptors signals are balanced by inhibitory receptors signals coming from the interaction with the self-molecules of the MHC class I complex. Neoplastic transformation or cellular infection can induce the expression of stimulatory ligands that overcome the inhibition induced by inhibitory receptors. In this case, an induced-cell recognition occurs . In many contexts both missing-self and induced-self recognition are likely to operate simultaneously to provide to NK cells the maximum ability to discriminate normal cells from transformed or infected ones.
NK cells can express on their surface different receptors able to recognize several polymorphic variants of MHC I molecules. Indeed, the human NK cell receptor repertoire is highly complex in each individual . In addition, NK cells express specific stimulatory and inhibitory receptors for various other ligands present on the surface of the target cells and the balance of inhibitory and stimulatory signals received by a NK cell determines the outcome of its interactions with target cells . These signals involve immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules and inhibitory receptors, other stimulatory receptors and adhesion molecules, such as KIR, immunoglobulin-like transcript (LIR), leukocyte-associated immunoglobulin-like receptor (LAIR), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM) . Thus, the activation program of NK cells derives from the integration of activator and inhibitor signals, which varies according to the nature of the interacting cells. In addition, NK cells also express cytokines and chemokines receptors that are crucial for the regulation of NK cell functions and Toll like receptors that mediate the production of IFN-g and increase cytotoxicity.
References:
1. Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57. 10.1038/nri3044 .
2. Turner JE, Rickassel C, Healy H, Kassianos AJ. Natural killer cells in kidney health and disease. Front Immunol. (2019) 10:587. 10.3389/fimmu.2019.00587.
3. Hoffmann U, Neudörfl C, Daemen K, Keil J, Stevanovic-Meyer M, Lehner F, et al. . NK cells of kidney transplant recipients display an activated phenotype that is influenced by immunosuppression and pathological staging. PLoS ONE. (2015) 10:e0132484. 10.1371/journal.pone.0132484.
4. Trojan K, Zhu L, Aly M, Weimer R, Bulut N, Morath C, et al. . Association of peripheral NK cell counts with Helios + IFN-γ(-)T(regs) in patients with good long-term renal allograft function. Clin Exp Immunol. (2017) 188:467–79. 10.1111/cei.12945 .
5. Turner JE, Becker M, Mittrücker HW, Panzer U. Tissue-resident lymphocytes in the kidney. J Am Soc Nephrol. (2018) 29:389–99. 10.1681/ASN.2017060599 .
Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.
NK cells were originally described as large granular lymphocytes with natural cytotoxicity against tumor cells. NK cells were later recognized as a separate lymphocyte lineage, with both cytotoxicity and cytokine-producing effector functions1. The acquisition of cell cytotoxicity during evolution has been associated with the development of highly sophisticated and robust mechanisms that control the initiation of the cytolytic processes and avoid tissue damage. Along this line, much progress has been made over the last fifteen years in the dissection of the mechanisms that allow NK cells to discriminate target cells from other healthy ‘self’ cells. These data have been instrumental in defining several recognition strategies and in the emergence of the ‘dynamic equilibrium concept’. The NK cell detection system includes a variety of cell surface activating and inhibitory receptors, the engagement of which regulates NK cell activities. Thus, the integration of antagonistic pathways upon interaction with neighboring cells governs the dynamic equilibrium regulating NK cell activation and dictates whether or not NK cells are activated to kill target cells2.
References:
1-Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989). Vivier, E., Nunes, J.A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).
2-Lanier, L.L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005). Sivori, S. et al. CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and den- dritic cells. Proc. Natl. Acad. Sci. USA 101, 10116–10121 (2004).
3-Gerosa, F. et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J. Immunol. 174, 727–734 (2005).
4-Hart, O.M., Athie-Morales, V., O’Connor, G.M. & Gardiner, C.M. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-γ production. J. Immunol. 175, 1636–1642 (2005).
●Definition:
Natural killer cells (also known as NK cells, K cells, and killer cells) are a type of lymphocyte (a white blood cell) and a component of innate immune system.
●Apotosis Vs cell lysis :
NK cells are cytotoxic; small granules in their cytoplasm contain special proteins such as perforin and proteases known as granzymes.
Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter, inducing apoptosis.
The distinction between apoptosis and cell lysis is important in immunology – lysing a virus-infected cell would only release the virions, whereas apoptosis leads to destruction of the virus inside.
●role in transplantation?
Natural killer cells play an important role in the human immune system, as they are involved in recognizing and killing harmful cells such as tumor cells. These harmful cells sometimes attempt to escape immune detection by decreasing MHC proteins, which are proteins expressed on cells that allow T cells to bind to, recognize, and tolerate itself. This mechanism renders the harmful cells invisible to T cells, but not to natural killer cells. Through their KIR receptors, natural killer cells can detect the absence of these MHC proteins and therefore kill the harmful cells. This constitutes a very important role.
Immune cells called natural killer cells contribute to organ rejection after transplantation because they miss “self” proteins on donor cells, according to a study appearing in an upcoming issue of JASN. A better understanding of this process may help clinicians prevent and treat organ rejection.
Transplanted organs are recognized by the immune system of the recipient as foreign or non-self, which leads to rejection of the organs. Rejection is prevented or treated with drugs that suppress the immune system, mostly targeting T immune cells; however, rejection can still occur despite such treatment, not only because T cells may not be completely suppressed by the therapy, but also because of antibodies and “natural killer cells” that target the donor tissue.
Natural killer cells play an important role in the human immune system, as they are involved in recognizing and killing harmful cells such as tumor cells. These harmful cells sometimes attempt to escape immune detection by decreasing MHC proteins, which are proteins expressed on cells that allow T cells to bind to, recognize, and tolerate itself. This mechanism renders the harmful cells invisible to T cells, but not to natural killer cells. Through their KIR receptors, natural killer cells can detect the absence of these MHC proteins and therefore kill the harmful cells. This constitutes a very important defense mechanism.
In transplantation, the donor cells in the transplanted organ are not escaping immune detection by decreasing MHC expression, but these donor cells express different MHC proteins than the recipient. The natural killer cells of the recipient therefore miss the “self” MHC on these donor cells and become active.
“This is exactly what we found in the study of 924 kidney transplantations: that the ‘missing self’ predicted by genetic analyses of the MHC molecules of donors and recipients, and the genetically determined KIR repertoire of the recipients, is predictive of rejection in kidney transplant biopsies,” said senior author Maarten Naesens, MD, PhD, of KU Leuven, in Belgium. “Therefore, the study shows that genotyping the donors and recipients not only for MHC (as is done in routine clinical practice), but also for KIR, will enable us to assess the presence or absence of ‘missing self,’ and improve the risk assessment of kidney transplant rejection.
●Reference: Callemeyn J, Senev A, Coemans M, et al. missing self–induced microvascular rejection of kidney allografts: a population-based study. JASN. 2021. doi: 10.1681/ASN.2020111558
NK cells:
are a component of the innate immune system that use a combination of
activating and inhibiting receptors specific for HLA class I molecules to differentiate
between autologous and allogeneic cells, thereby controlling their activation in response
to foreign tissues .
When activated, NK cells produce cytotoxic effector molecules without the need for
priming by antigen presenting cells.
This process takes place before the engagement his process takes place before the
engagement of adaptive immune system.
They are 5–20% of lymphocytes in the spleen, liver, and peripheral blood and are
present at lower frequencies in the bone marrow, thymus, and lymph nodes.
Studies in mice have shown that NK cells can undergo clonal expansion to create innate
Memory, analogous to memory responses of the adaptive immune system.
Role of NK cell in transplant is controversy, recently NK cells show contribution to the
rejection of kidney and lung transplants. Infiltration of kidney allografts by cytotoxic
CD56+ cells producing high amounts of granzyme A and B and interferon-gamma has
been identified as a feature of acute rejections in kidney transplants.(1).
They mediate the antibody-dependent cellular cytotoxicity (ADCC) of targets through
FcγRIII.(CD16), a receptor that binds the Fc portion of antibodies.
Functional aspects of NK in mediating allograft tolerance:
Host NK cells, through their killing of allogeneic APCs, limit the persistence of donor-
derived DCs, therefore contributing to the induction of transplant tolerance.
NK cells and immunosuppressive drugs:
as it has recently been demonstrated that steroids and Calcineurin inhibitors limit the
function of IL-2-activated NK cells.(2).
References:
1- Adenugba,AkinbamiPhD..NKCells inTransplantation.Transplantation: Octob. 2017 –
Volume 101 – Issue 10 – p 2262-2264.
2- Johann Pratschke,Diana Stauch,Katja Kotsch.Role of NK and NKT cells in solid
organ transplantation .Transplant international .03 August 2009.
Natural killer cells
• effector lymphocytes deriving from common lymphoid progenitors
• represents 5-10% of circulating lymphocytes
• natural cytotoxic cells but do not require antigen exposure in mediating effect
• accomplish cytolytic effector activity through 2 mechanism
o Direct lysis -recognition of HLA class 1 molecules by KIR( killer cells immunoglobulin-like receptors), inhibitory receptors on NK cell inhibits cytotoxic activity and maintains the recognition of self
o Antibody dependant cellular cytotoxicity (ADCC)- interaction between Fc receptor FcγRIII (CD16) expressed on NK cells and Fc fragment of apsn antibody recognising foreign antigens on target cells induces lysis of these cells
NK cells in Kidney Transplantation
• Are heterogenous population of innate lymphocytes with subset-specific functional roles and with complex functions during haemostatic and pathological conditions
• Still controversial in role in immune reactivity to solid organ transplantation
• May promote allograft injury
• Evidences showed that may play a important role in the priming of allograft tolerance
• Post transplantation, NK cell subsets can transform at the peripheral level which not able to do by pre transplant cells and these transformation will affect both the number and the phenotype, so this explains that NK cell immunoregulatory characteristic can influence the graft outcome
NK cells involvement in Acute or chronic allograft rejection
ABMR
• Yagisawa et al showed presence of both NK cell and DSA induced acute kidney graft rejection in a mice model of kidney transplantation, but DSA alone can may lead to late graft failure but not acute mediated rejection
• Influence maturation of DCs and lead to activation of T cells
• NK cell are early source of Th1-type immune response induced by IFN-g
• directly interact with CD4+ T lymphocytes leads to reactivity and induction of acute rejection pathway
• Human ABMR through CD16 expression which triggered by anti-HLA antibodies (DSAs) contributed to graft loss- proposed by Turner et al
• Nk cells have been identified in peritubular capillaries and DSA seen bind to the graft endothelial cells of the biopsies of ABMR
• AMBR showed increased CD56bright and CD56dim
TCMR
• IHC of the graft showed TCMR is characterised by higher number of CD56+ and CD57+ cells within the interstitial compartment associated with interstitial and tubulitis – 0.56cells/mm2 both interstitial and glomerular level associated with worse graft outcome
• Biopsies from patient T cell have shown increased absolute number of CD 56 bright
• CD56bright NK cells has role in TCMR trough secretion of pro inflammatory molecules such IFN-g,leads to increase recruitment of alloreactive T cells and up regulate MHC 1&2 on graft target cells making more prone for cytotoxic killing
NK cells in influencing transplant tolerance
• NK cells have potent immunoregulatory properties that induces tolerance
• Skin transplantation model in mice- recipient NK cell can contribute to the induction of graft tolerance by killing APC
• Activated NK cells can destroy donor derived DCs through direct lysis mechanism lead to tolerance indiction
• IL-10 produced by NK cells could have role in maintenance of transplant tolerance
References
Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L. and Stallone, G., 2020. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Frontiers in Immunology, 11.
Kidney Transplantation: Principles and practice by Stuart J.Knechtle
Natural killer cells (NK) are lymphocytes involved in innate immune response. NK regulate the allo-immune response in kidney transplant recipients.
Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss.NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Paola Pontrelli P ,Federica Rascio F. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 23 July 2020
NK cells are part of the innate immune system. It from lymphoid progenitor together with T and B lymphocytes. They enhance B and T cells responses, and they have specific anti-cancer and anti-viral activities.
NK cells are effector lymphocytes and account 10-15% of circulating lymphocytes and don not need antigen exposure for their activation unlike the cytotoxic T cells.
Role of NK cells in transplantation varies from rejection to tolerance. NK cells play a role in both T cell mediated rejection and antibody mediated rejection.CD56 bright NK cells are able to secrete proinflammatory molecules such as IFN-g which play a role in TCMR while CD56 dim / CD 16 NK cells can interact with DSA in the graft endothelial cells activating the Antibody dependant cellular cytotoxicity and hence ABMR. On the other hand, NK cells and Treg can activate each other promoting tolerance and also the activated NK cells have the ability to kill the dendritic cells increasing the potential of tolerance.
Immunosuppressive drugs have the ability to change the phenotype of NK cells and also reduce their number post transplantation so follow up of NK cells number and function can predict the risk of infection and malignancy post transplantation.
Ref:
Frontiers | The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation | Immunology (frontiersin.org)
Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. They have a role in anti-viral and anti-tumor defense mechanism , they also regulate several aspects of the allo-immune response in kidney transplant recipients. NK cells have a key role in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Reference:
The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation
Paola Pontrelli, Federica Rascio, […], and Giovanni Stallone
NK (natural killer) cells are lymphocyte-like cells capable of killing some targets, notably virus-infected cells and tumor cells. Natural killer cells share features of both lymphocytes and innate immune cells. New studies show that NK cells can discriminate between self and foreign tissues and play a key role in the initiation and regulation of adaptive immune responses after solid organ transplantation.
Natural killer (NK) cells are of special interest because, in addition to cytokine production, NK cells can directly target the transplanted tissue through the balance of activating and inhibitory receptors and their ligands expressed or not expressed by the graft. In solid organ transplantation (SOT), the inhibitory KIRs expressed by NK cells can bind to the corresponding MHC-I expressed by the graft which prevents NK cell activation. The absence of the cognate MHC-I ligand induces a ‘missing self-situation’ and activated NK cells target the graft. However, more recent studies demonstrate that NK cells become activated early after organ transplantation and can contribute to the cell-mediated alloresponse and acute rejection process.
The mechanism of NK cell alloreactivity is also mediated by an indirect pathway, i.e. through the production of pro-inflammatory cytokines. The secretion of IFN- and TNF- by NK cells is likely to induce and upregulate the expression of MHC molecules and costimulatory receptors on APCs, thus promoting the maturation efficacy of professional APCs (dendritic cells and B cells) and presumably nonprofessional APCs (endothelial cells) which enhance direct and indirect alloresponses by T cells. NK cells can also kill Foxp3+ regulatory T cells, depending on the activation status of NK cells.
More recently, NK cells have been shown to be crucial for graft survival. CD28-deficient mice readily reject an MHC mismatched heart allograft; in this model, rejection can be prevented by the depletion of host NK cells. Currently, there is no doubt that NK cells can contribute to acute and chronic allograft rejection in rodent models. In human SOT, the exploration of NK cells is much more limited. The presence of NK cells in kidney biopsy of acute cellular rejection is rare, but recent data demonstrate that NK cells and macrophages are selectively increased in peritubular capillaries of kidney biopsies following antibody-mediated rejection situations.
The absence of inhibition with the presence of an activating receptor induces the killing of the allogeneic tissue. The combination of activating or inhibitory KIRs defined by A or B haplotype and the expression of their cognate MHC ligands can theoretically lead to alloreactivity potential against the graft. Recent publications have shown a correlation between specific KIR/HLA-C and graft survival in kidney and liver transplantation.
References:
1. Villard J. The role of natural killer cells in human solid organ and tissue transplantation. Journal of innate immunity. 2011;3(4):395-402.
2. Maier S, Tertilt C, Chambron N, Gerauer K, Huser N, Heidecke CD, Pfeffer K: Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28–/– mice. Nat Med 2001;7:557–562
What are the NK cells?
NK cells are subtype of lymphocytes but part of innate immunity
They represent around 5-10% of peripheral circulating lymphocytes
And it get maturation in 2ry lymphoid organ and divided into 3subtypes according to Cd 56/Cd 11b/Cd27 Rc exposed on its surface
NK1:Cd 56 dim/Cd11b +ve/Cd 27-ve…it secrets proinflammatory cytokines and play role in graft rejection
NK2:Cd56bright/Cd11b-ve/Cd27-ve
NKreg: Cd56bright Cd11b-ve Cd27+ve and secrets IL10 and play role in tolerance
What’s it’s role in immune system
NK cells don’t need Ag on APC to get activated.it carry stimulatory singals and inhibitory signals bind to cells by multiple ligands and the net balance decided its action
Usually NK interact with self class 1 HLA on self cells which stimulate the inhibitory signals and absence of self HLA class 1 like on damaged cell/neoplasm cell/virally infected cells (after HLA class 1 downregulation) lead to NK stimulation which elicit it’s action through 3 main mechanisms
1/direct cell lysis: switch to cytotoxic Nk and cause destruction of cell membrane
2/complement dependent cellular cytotoxicity: antibodies attachment to foreign HLA and Nk attach to fc region through cd16(fCyR111) activating its cytotoxicity
3/it secrets inflammatory cytokines like interferone gamma causing macrophages and denderitic cells migration also Naive t cell maturation into Th1 which leads to adaptive immunity involvement.
Role of kidney tranplantation
Play important role in graft rejection/tolerance/immune system monitoring
1)graft rejection: NK switching to cytotoxic Nk cause graft destruction and more exposure of alloantigen also invasion of macrophages and maturation of Naive tcell into effector Th1 and involvement of adaptive immunity both cellular and humoral immunity.also IgG elicit part of it’s action by Nk after bind between fc region and cd16 causing C4d negative (independent) ABMR
Graft tolerance:it attack and destroy donor derived APC post transplant and inhibit direct pathway stimulation of immunity which usually associated with acute rejection post transplant also NKreg secrets IL10 which elicit inhibitory effect on adaptive immunity.
Immunosuppressant medications monitoring:CNI cause decrease NK number and mTOR cause change in it’s phenotyping and it’s function and cytokines secretion which lead to increase risk of infection and malignancy
Studies are ongoing to monitor Nk number and function to be used as a sensor to drugs doses in the future.
Reference:
1-Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cell in the immune response in kidney transplantation. Front Immunol 2020;11:1454.
2- Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235:286
3- Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2:735.
4- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
Thank you Rami please try to organize your information like so:
name of cell
Origin
Mechanism of action
Related to rejection,which type ,tolerance,accommodation,monitoring,
Mechanism of each controlling drug and cotrevesial action.
Natural killer cells (NK) as the name implies they have a direct cytotoxic effect on the target, no need for antigens. In addition to their antiviral and anti-tumor effects, they play a role in alloimmune response in kidney recipients.
Natural killer cells (NK) represent a population of lymphocytes involved in the innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the alloimmune response in kidney transplant recipients.
They accomplish cytolytic activity either by direct lysis or antibody-dependent cellular cytotoxicity
They have KIR (killer cell immunoglobulin-like receptor) which recognizes HLA class I antigens.
They express CD16 (FcγRIII) Fc receptor through which the interact with target Fc fragment causing antibody-dependent cellular cytotoxicity.
Reference?
NK cells are group of lymphocytes which play important role in solid organ transplantation, there are 2 types of NK cells :CD 56 bright and CD 56 dim the dim one comprises 90% of blood and spleen .
NK cells play role in innate immune system also they have defense property against virus and tumor( have the ability to distinguish allogenic cells from self cells) .
NK cells can effect on both T cell mediated rejection (acute or chronic) and Ab mediated rejection .
Reference?
Natural killer lymphocyte plays an important role in acute and chronic cellar rejection and in antibody mediated rejection and also important in graft tolerance.
NK lymphocyte are cytotoxic cells whose activation doesn’t require antigen to elicits a reaction, unlike cytotoxic T cells . NK cells has inhibitory receptors on the surface , and once this receptor is engaged with HLA class I , it inhibit the Cytotoxic function of the NK cells , so no damage to the self cells . But if NK cells encounter cells that don’t have HLA ( like cancer cells ) they destroy these cells (missing self).
Also NK cells could bound to Fc region of the antibodies and damage cells that bound to the antibody , So NK cells participate in the antibody mediated rejection.
NK cells also secrete INFgamma and TNF that activates T cells , dendritic cells , and macrophages. also secrete many chemotactic factors that attract inflammatory cells toward the graft. (acute and chronic cellular mediated rejection)
On the other hand , NK cells are important in graft tolerance: NK cells can kill APC of the donor, thus preventing these cells from presenting HLA antigens to the T cells , so they prevent T cell activation. Also NK cells produce IL10 which is associated with graft tolerance. Also there is cross talk between NK cells and Treg cells that leads to activation of Treg and induction of graft tolerance.
Reference :
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L and Stallone G (2020) The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol. 11:1454. doi: 10.3389/fimmu.2020.01454
NK
Represent about 5-10% of circulating lymphoctys , they are important part of innate immune system ,have cytotoxic effect that do not require antigen exposure for stimulation .NK cells can differiate into three types : Natural killer type-1 (NK1) secreting IFN-g , NK type-2 (NK2) producing various cytokines as IL-5 and IL-13 and NK regulatory cells (N K reg ) that has immune regulatory function via cytokines secretion and cell-to-cell contact . Phenotypically , Nk are classified into (high-density CD56bright ( 90% of NK population ) and low density CD56dim cells ( 90 % of all NK population ) that are predominant in prepheral blood , have cytotoxic effects and express high levels of FcγRIII (CD16) so are involved in antibody mediated graft injury (1)
The effect of NK on kidney transplantion is variable , they can induce graft injury and meanwhile may enhance development of operational tolerance.
NK can produce graft injury either
1- Acute graft injury through Antibody-dependent cellular cytotoxicity (ADCC) in presence of DSA through the expression of CD16 or through infiltrate the graft causing direct graft damage.
2- Chronic graft injury as They can enhance migration of immune cells as dendritic cells into the graft producing an increasing alloimmune response as well as enhancing activation of T cells via promoting maturation of dendritic cells and secretion of IFG , this eventually will lead to chronic AMR and chronic graft rejection.
NK may exert beneficial effect on graft function through downregulating CD8+ T-cell proliferation by competing for IL15 and they can inhibit clonal expansion of antigen-stimulated T cells as well as killing dendritic cells. (2)
1-Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L., & Stallone, G. (2020). The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Frontiers in immunology, 11, 1454. https://doi.org/10.3389/fimmu.2020.01454
2- Emilie Dugast, Gaëlle David, Romain Oger, Richard Danger, Jean-Paul Judor, et al.. Broad Impairment of Natural Killer Cells from Operationally Tolerant Kidney Transplanted Patients. Frontiers in Immunology, Frontiers, 2017, 8, pp.1721. ⟨10.3389/fimmu.2017.01721⟩. ⟨hal-01712225⟩
What are the NK cells
Nk cells are lymphocytes involved in innate immunity .
The majority are CD8 positive and they variably express NK-cell- associated antigen s ,including CD56 and CD57 .
In the peripheral blood NK cells can express CD4 molecules on their surface.
They do not carry TCR or BCR.
They express complementary receptors . the activating receptors recognize ligands induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class1 molecule.
Allogrft tissure express – non self MHC proteins ,they do not engage inhibitory receptor on the donor NK.
They are either activated by immunoreceptor tyrosine-based activating motifs(ITAMs) or inhibited by immunoreceptor tyrosine-based inhibitory motifs .
NK cells secret a wide variety of cytokines as TNFy,TNFa,Gm_CSF,IL10, IL% and IL13 and chemokines such as MIP-1a ,MIP-1B,IL-8.
TNFa activates macrophage causing cell lysis. Also promote direct NK tumour cell killing.
They have anti viral and anti neoplastic role.
They have short life span of 2 weeks.
Deficiency of NK cells increase the susceptibility to virus infection.
The role of NK in kidney transplantation;
Early activation of NK cells post kidney transplantation is associated with killing of allogenic target cells and release of immune modulatory cytokines and chemkines which can contribute to either rejection or tolerance.
They can activate T-cells through the production of cytokines . They can express Co-stimulatory molecules allowing them to activate T-cells
Transplant rejection usually type 1V hypersensitivity reaction(delayed) mediated by T-cells in which the transplant recipient”s T-cells become alloreactive ,recognizing major MHC antigens on the donated organ and promote local immune and inflammatory responses to defend against the
Referance;
Pmc https//www.ncbi.nlm.nih.gov.
Kidney transplant hand book 6 edition
NK cells are natural cytotoxic cells and part of innate immune system to recognize HLA molecules. They can induce rejection producing IFN-γ, perforin and granzyme by cytotoxic CD56+ cells. Defects of NK cells is producing perforin can induce non-Hodgkin lymphoma as complication of immunosuppression.
Some studies showed that donor NK cells detects HLA class Ι as a result of killer immunoglobulin-like receptors (K1Rs). Their cytotoxic activity is through HLA class recognition by K1Rs and interaction between NK cells CD16 and FC fragment of Abs. Human NK cells are CD3-/CD56+/CD335 (NKp46) mononuclear cells. NK cells can participate in cell mediated or antibody mediated rejection. They can activate T cell and by producing IF-N –γ increase reactivity of CD4+ T cells. A subset of NK cells (NK CD56dim) with CD16 can induce ADCC. Infiltration of CD56+ NK cells is seen in cell-mediated rejection in tubulointerstitium of kidney and confirms role of these cell in T cell rejection. CD56 bright NK cells are important for TCMR by IFN- γ secretion.
NK cell can be active in transplant tolerance. They can kill donor dendritic cells produce IL-10 and influence Tregs. These activities are contributing in tolerance. NK cell can kill allogenic APCs that induce T cell activation. IL-10 can induce regulatory dendritic cells. In tolerant patients NK cells show reduced expression of NKP46 and CD16 that results in reduction of cytotoxicity function and IFN-γ . NK cells are able to induce CD4+ CD25 .FOXP3+ T cells which have regulatory function and can induce tolerance.
References:
1.Pontrelli, P., Rascio, F., Castellano, G., Grandaliano, G., Gesualdo, L., & Stallone, G. (2020). The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. In Frontiers in Immunology (Vol. 11).
2.Adenugba, Akinbami PhD1 NK Cells in Transplantation, Transplantation: October 2017 – Volume 101 – Issue 10 – p 2262-2264
NK cells represent 5-10% of circulating lymphocytes.
They are one of the components of innate immunity, natural cytotoxic cells that don’t require antigen exposure. (1)
NK cells can contribute in both T cell mediated and antibody mediated rejection. (2)
Antibody mediated rejection:
NK cells influence maturation of dendritic cells and activation of T cells (3)
they secrete IFN-g leading to Th1 immune response and increase the activity of CD4+ T lymphocytes (4)
T cell mediated rejection:
NK cells secrete proinflammatory molecules increase recruitment of alloreactive T cells, upregulate HLA alloantigen (MHC class I and II) on graft cells making them more prone to cytotoxic lysis (5)
NK cells have immunoregulatory functions that may help in allograft tolerance. (6)
NK cells play a role in cancer defense and incidence of cancer increase after transplantation, (7) monitoring NK cells number and function in transplant patients may have a role in controlling and prediction of onset of infection and neoplasia. (8)
The evaluation of number and function of NK cells in peripheral blood of recipients may inform about immune state induced by immunosuppressive drugs and may help to achieve equilibrium between graft survival and reduction of risk of developing malignancies or infections. (9)
(1) Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels
with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57.
(2) Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7.
(3) Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM.
Highlighting the role of DC-NK cell interplay in immunobiology and
immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018).
(4) Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
(5) Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Specialized roles of human natural killer cell subsets in kidney transplant rejection. Front Immunol. (2019) 10:1877
(6) Beike JN, Kuhl NR, Van Kaer L, Gill RG. NK cells promote islet allograft toerance via a perforin-dependent mechanism. Nat Med. (2005) 11:1059– 106.
(7) Grulich AE, van Leeuwen MT, Falser MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-anlysis. Lancet. (2007) 370:59–67.
(8) Stallone G, Infante B, Grandaliano G. Management and prevention of posttransplant malignancies in kidney transplant recipients. Clin Kidney J. (2015) 8:637–44.
(9) Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The role of natural killer cells in the immune response in kidney transplantation. Frontiers in Immunology. 2020 Jul 23;11:1454.
Natural killer cells are lymphoid cells they express complementary activating and inhibitory receptors. It activated when infiltrate the graft by binding of alloantibodies there to fcRs on NK; used to kill their target by performin,granzyme and IFN gama ;they have cytotoxic and memory function mainly in the viral infections.it play secondary role in rejection
Thanks Nazik
Please expand on your answer. No references as well. This is a suboptimal answer
NK cells are lymphoid cells that do not carry TCRs or BCRs but instead express complementary activating and inhibitory receptors. Activating receptors recognize ligands induced on many cell types during inflammation or infection, while inhibitory receptors bind self-MHC class I molecules.
NK cells are stimulated when the balance between activating and inhibitory signals is tilted in favor of the former. Since allograft tissues express non-self MHC proteins, they
do not engage inhibitory receptors on donor NK, leading to NK-cell activation. Therefore, in contrast to alloreactive T and B lymphocytes which respond to nonself, NK cells respond to missing self.
NK cells that infiltrate allografts can also be activated by binding of alloantibodies in the graft to FcRs on NK cells. Once activated, NK cells kill their targets by secreting the same molecules utilized by CTL (perforin, granzyme, and IFNγ) and differentiate to memory cells. Despite their cytotoxic and memory functions, NK cells appear
to have a secondary role in allograft rejection.
Two subsets of NK cells exist in humans, CD56bright cells and CD56dim cells, with CD56dim NK cells comprising approximately 90% of blood and spleen NK cells. This subset expresses FcγRIIIA (CD16) and undergoes antibody-dependent cell-mediated cytotoxicity (ADCC), the targeted release of cytotoxic molecules in response to FcγR ligation by IgG-opsonized cells.
Thank you for mentioning this fact; “NK cells respond to missing self.”
How do you think this is implicated in graft rejection?
NATURAL killer cells are group of lymphocytes involved in innate immune response
Normally they play key role as anti tumors and antiviral .
After transplantation, they play a key role in graft damage , alloreactive NK cells can direct the adaptive immune response and accumalate other cells thus potentiating immune mediated graft injury leading to eventually chronic Ab mediated rejection and graft loss .
Natural killer cells can infiltrate the graft and causes direct injury
Specific subsets of NK cells may help in graft tolerance .
Transplant immunosuppressive drugs affect NK cells and so increases incidence of post transplant viral infections and malignancy
Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response.
Role of Natural killer cells (NK):
The NK cells accomplish their cytolytic effector activity through two main mechanisms of action :
1. Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
2. Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
Thanks, well done
I quote this from your reply “ immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection”.
We need a balanced immunosuppression to achieve excellent graft survival while preventing overzealous immunosuppression that leads to increased infection and malignancy.
What are the NK cells?
NK cells or the natural killer cells are a subset of circulating lymphocytes representing a component of innate immunity. They constitute approximately 5-10% of the lymphocytes and cause cell lysis. The balance between inhibitory and stimulatory signals on NK cells is responsible for final outcome (cell lysis versus no lysis).
NK cell maturation occurs in medulla of secondary lymphoid organs (lymph node, tonsil, spleen). Mature NK cells are of 3 types depending on the presence or absence of CD56, CD11b and CD27:
1) NK-1: CD56dim CD11b+ CD27-. They have activating role, producing interferon gamma.
2) NK-2: CD56bright CD11b- CD27-. They have inhibitoy role, producing IL-5 and IL-13.
3) NKreg: CD56bright CD27+. They have immune regulatory role via cytokine secretion and cell to cell contact.
What is their role in transplantation?
NK cells have multifaceted roles in kidney transplantation including both in rejection as well as tolerance.
a) Role in rejection: NK cells influence maturation of dendritic cells leading to T cell activation. They also release interferon gamma causing Th1 type response. They interact directly with CD4+ cells leading to increase in their reactivity and acute rejection
DSA bound to graft endothelial cells in peritublar capillaries interact with CD16 on CD56dim NK cells leading to antibody dependent cell-mediated cytotoxicity and antibody mediated rejection.
CD56bright CD57+ NK cells have role in T cell mediated rejection by releasing interferon enhancing the recruitment of alloreactive T cells and HLA antigen to the target cells in graft leading to cytotoxic killing.
b) Role in tolerance: Activated NK cells can directly lead to lysis of donor-derive dendritic cells, ushering in transplant tolerance. Role of increased production of IL-10 by NK cells has also been seen in inducing tolerance.Tolerance due to NK cells has been shown to be relevant especially in first 3 weeks post-transplant.
c) Role with immunosuppression: NK cells act as sensors for immunosuppression. It has been shown that patients on cysclosporin have decreased number of NK cells and decreased CD56dim/ CD56bright ratio at 1 year post traansplant affecting their cytotoxic activity with time. Patients on mTOR inhibitors have been shown to have NK cells with modified degranulation properties with reduced interferon gamma production.
So, in future monitoring NK cell number and their type could become a handy tool to prevent side-effects of immunosuppression like infectiona and malignancies.
Reference:
Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cells in the immune response in kidney transplantation. Fron Immunol 202;11:1454.
Thanks Amit
I like your reflection “in future monitoring NK cell number and their type could become a handy tool to prevent side-effects of immunosuppression like infectiona and malignancies”.
Natural killer (NK) cells have potent effector functions and play
a key role in a range of immune responses, including those against
pathogens and cancers .
NK cells have two key effector functions, which are the cytotoxic lysis of target cells and the release of inflammatory cytokines that amplify the immune response, including interferon (IFN)-c
NK cells provide innate immunity against abnormal cells, where their activation depends on the integration of signals arising from activating and inhibitory receptors on their cell surface.
ROLE OF NATURAL KILLER CELL IN GRAft rejection,
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection
NK cells can also influence maturation of dendritic cells and the subsequent activation of T cells . Moreover, NK cells are an early source of IFN-g, which drive a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes , increasing their reactivity, and these activities can induce acute rejection mechanisms.
despite their essential role in allograft rejection, NK cells might also promote allograft tolerance.
Donor antigen-presenting cells, in the absence of host NK cells, can survive and directly induce the activation of alloreactive T cells that are resistant to co-stimulatory blockade treatment
Thus, in those models in which NK cells have an altered function or are reduced, it will be difficult to obtain tolerance toward a MHC mismatched graft. After transplantation, in fact, both antigen presenting cells and T cells may represent potential targets of NK cell regulation
Activated NK cells can kill donor-derived dendritic cells through direct lysis, thus dampening the immune response and promoting a tolerogenic environment
Clin J Am Soc Nephrol 10: 1459–1469, 2015. doi: 10.2215/CJN.04680514
Front. Immunol., 23 July 2020 | https://doi.org/10.3389/fimmu.2020.01454
Thanks Mohammed for your effort and hard work. I strongly advise you write in your own words.
Natural killer (NK) cells are effector lymphocytes represent 5–10% of circulating lymphocytes.
NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect (1).
Thay are the main defence against viral infections and tumours.
NK cells produce cytokines like IFN-y, TNFa, and GMCSF which activate T cells, dendritic cells, macrophages, and neutrophils to enhance adaptive immune system
The NK cells perform their cytolytic effector activity through two main mechanisms of action (2) :
First Direct lysis. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self” instead, the absence of class I HLA molecules on target cells (e.g., cancer cells) prevents inhibitory signals from switching off the cytotoxicity of NK cells.
Second Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
inhibitory or stimulatory receptors on Nk cell surface determine the fate of the target cell
When signals from both receptors are equal as in normal self cells these cells are protected while neoplastic and infection cells induce the stimulation signals causing cell lysis(3) .
NK cells can be distinct into subsets characterized by different expression of cell surface proteins and cytokines
Natural killer type-1 (NK1) with activating signals, are mainly CD56dim CD11b+ CD27− cells produce IFN-g.
NK type-2 (NK2) , with inhibitory signals, are mainly CD56bright CD27− CD11b− and produce type-2 cytokines, including IL-5 and IL-13;
NK regulatory cells (NKreg with CD56brightCD27+ NK cells and play their immune regulatory effect by cytokines secretion or cell-to-cell contact (4).
NK cell in kidney disease :
NK cell present in high number in kidney biopsies from patients with chronic kidney disease both NK CD56dim and CD56bright cells were increased in fibrotic renal tissue, but only CD56bright correlated significantly with loss of kidney function (5),
NK cell role in kidney transplantation:
• Yagisawa et al. demonstrated, in a mice model of kidney transplantation, that acute kidney allograft rejection is induced by the presence of both NK cells and donor specific antibodies (DSA), whereas in the absence of NK cell activation the presence of DSA alone cannot induce acute antibody-mediated rejection, although it can still lead to late graft failure (6).
NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR (7)
CD56dim/CD16 NK cells the main NK subset involved .
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection .
• NK cells can increase maturation of dendritic cells resulting in activation of T cells (9).
•NK cells are source of IFN-g, which drive a Th1-type immune response.
•NK cells can interact directly with CD4+ T lymphocytes , increasing their reactivity, and these activities can induce acute rejection.
•acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis (10).
NK cells may also play a role in tolerance:
•Activated NK cells can kill donor dendritic cells through direct lysis , thus dampening the immune response and promoting a tolerance
•NK cells regulation could also affect recipient dendritic cells, thus influencing allograft antigen presentation (11).
•The maintenance of tolerance could be also associated with the production of IL-10 by NK cells which promote the development of regulatory dendritic cells .
NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .
It is therefore possible that NK cells per se do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response (8).
Immunosuppression Influence NK Cell Behavior?
Immunosuppressive drugs modulate the phenotype of NK cells after kidney transplantation, suggesting that NK cells can serve as sensors for immunosuppression and can be considered for personalized immunosuppression therapy adjustment(12) .
In fact, among kidney transplant recipients with a compared to healthy controls, patients receiving tacrolimus showed reduced expression of CD16 and CD56 on NK cells than patients treated with cyclosporine or tacrolimus in combination with mTOR inhibitors .
In addition, the presence of mTOR inhibitors in vitro also had functional consequences regarding de-granulation and IFN-g production (12)
In patients treated with cyclosporine compared to patients treated with tacrolimus, the number of NK cells as well as the ratio CD56dim/CD56bright is lower and the cytotoxic activity is reduced 1 year after transplantation .
Reference
1 Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8? T cells. Nat Rev Immunol. (2011) 11:645–57.
2 Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. (2016) 16:7–19.
3 Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol. (2006) 6:520–31.
4 Fu B, Tian Z, Wei H. Subsets of human natural killer cells and their regulatory effects. Immunology. (2014) 141:483–9.
5 Law BMP, Wilkinson R, Wang X, Kildey K, Lindner M, Rist MJ, et al. Interferon-γ production by tubulointerstitial human CD56(bright) natural killer cells contributes to renal fibrosis and chronic kidney disease progression. Kidney Int. (2017) 92:79–88.
6 Yagisawa T, Tanaka T, Miyairi S, Tanabe K, Dvorina N, Yokoyama WM, et al. In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection. Kidney Int. (2019) 95:350–62.
7 Yazdani S, Callemeyn J, Gazut S, Lerut E, de Loor H, Wevers M, et al. Natural killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney Int. (2019) 95:188–98.
8 Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7.
9 Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM. Highlighting the role of DC-NK cell interplay in immunobiology and immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018).
10 . Dos Santos DC, Saraiva Camara NO, David DSR, Malheiros DMAC. Expression patterns of CD56+ and CD16+ cells in renal transplant biopsies with acute rejection: associations with microcirculation injuries and graft survival. Nephrology. (2017) 22:993–1001.
11 Hadad U, Martinez O, Krams SM. NK cells after transplantation: friend or foe. Immunol Res. (2014) 58:259–67.
12 Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, et al. The Peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs. Front Immunol. (2013) 4:46.
Well done Shereen
NK cells are cytotoxic cells, they do not require antigen exposure to mediate their effectnor complement to exert its damaging effect.
They accomplish their lytic effect through direct lysis and antibody dependent cellular cytotoxicity
NK cells can cause allograft injury,on the other hand NK cells may have a role in the priming of graft tolerance.
NK cells can contribiute to the pathogenesis of acute and chronic T cell-mediated and antibody-mediated rejection.
NK cells has an effect on maturation of dendritic cells and activation of T cells ,also NK cells produce IFN-g,that stimulate a Th1-type immune response and interact directly with CD4+ T lymphocytes leading to acute rejection.
NK role in antibody mediated rejection(ABMR) is started through expression of CD16,this is triggered by DSAs . NK cells was found in the peri-tubular capillaries of the biopsies of patients with ABMR.
NK cells may play also a role in the pathogenesis of T cell-mediated rejection.
A study demonstrated that biopsies from patients with T cell-mediated rejection showed an increased number of CD56bright NK cells while in the biopsies of those with antibody-mediated rejection both CD56bright and CD56dim NK cells were increased.
Kidney biopsies from ABMR patients revealed significant enrichment of NK cell transcripts, and activated NK cell infiltration can differentiate ABMR from TCMR and can indicate graft failure occurrence.
Suppression of NK-cell activity can improve the kidney graft survival
Mean while NK cells have potent immunoregulatory effects leading to tolerance induction by killing APCs
Tregs suppress NK cells and inhibit their effector functions
A direct correlation between NK cells and Tregs in inducing tolerance is controversial ,it is possible that there is a mutual antagonism between NK cells and Tregs.
NK cells can induce tolerance by blocking dendritic cells and T cells that could start rejection in the first 3 weeks after transplantation , while Tregs would maintain the long-term tolerance .
Reference
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L and Stallone G (2020) The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol. 11:1454
Excellent Doaa
Natural killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5–10% of circulating lymphocytes. NK cells are natural cytotoxic cells, but, unlike cytotoxic T lymphocytes, they do not require antigen exposure to mediate their effect.
NK cells may play also a role in the pathogenesis of T cell-mediated rejection. Immunohistochemical characterization of graft infiltrating cells demonstrated that patients with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, both characteristics of T cell-mediated rejection.
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
Yagisawa et al. recently demonstrated, in a mice model of kidney transplantation, that acute kidney allograft rejection is induced by the presence of both NK cells and donor-specific antibodies (DSA), whereas in the absence of NK cell activation the presence of DSA alone cannot induce acute antibody-mediated rejection, although it can still lead to late graft failure.
NK cells can also influence the maturation of dendritic cells and the subsequent activation of T cells. Moreover, NK cells are an early source of IFN-g, which drive a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes, increasing their reactivity, and these activities can induce acute rejection mechanisms.
Halloran PF. T cell-mediated rejection of kidney transplants: a personal viewpoint. Am J Transplant. (2010) 10:1126–34? DOI: 10.1111/j.1600-6143.2010.03053.x
PubMed Abstract | CrossRef Full Text | Google Scholar
Yagisawa T, Tanaka T, Miyairi S, Tanabe K, Dvorina N, Yokoyama WM, et al. In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection. Kidney Int. (2019) 95:350–62. DOI: 10.1016/j.kint.2018.08.041
PubMed Abstract | CrossRef Full Text | Google Scholar
Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, Neves BM. Highlighting the role of DC-NK cell interplay in immunobiology and immunotherapy. In: Chapoval SP, editor. Dendritic Cells. IntechOpen (2018). DOI: 10.5772/intechopen.78804
CrossRef Full Text | Google Scholar
Well done
How do NK cells induce their effector actions on cells?
How are they involved in ABMR? For example, at which compartment of glomerular histology should you look for NK cells activation?
How do NK cells induce their effector actions on cells?
NK cells mainly act by releasing Th1 type cytokines (Interferon Gamma, TNF, GMCSF) activating T cells, dendritic cells, macrophages and neutrophils. They also produce cytokines like CCL3, CCL4, CCL5 which are responsible for attraction of myeloid cells and effector lymphocytes towards the inflamed tissue.
How are they involved in ABMR? For example, at which compartment of glomerular histology should you look for NK cells activation?
In Antibody mediated rejection, NK cells act via CD16. DSA bound to graft endothelial cells interact with the CD16 on NK cell leading to antibody dependent cell mediated cytotoxicity against the graft. NK cells can be seen in the peritubular capillaries.
Reference:
Ponterlli P, Rascio F, Castellano G, et al. The role of natural killer cell in the immune response in kidney transplantation. Front Immunol 2020;11:1454.
Excellent, thank you, Amit.
NK cells can have the effector function With the help of the CD16cytotoxic activity which is AB mediated in the presence of DSA antibody and lead to microvascular injury at the level of endothelial cells in ABMR and. Not necessarily to be complement mediated
Binding of DSA to the graft endothelium induces the expression of molecules attracting NK cells and other cells and expression of ligands that engage in NK cell activation receptors. Activation of NK cells through specific ligands and CD16 stimulate IFN-γ production and expression of other molecules that further enhance inflammation & mediating graft injury. In graft biopsy there will be microcirculation inflammation & tubulitis
References:
Well done
NK cells exert their cytolytic effector action through
The lytic function depend on cytolytic molecules granzymes and perforins which lead to production of several inflammatory cytokines.
NK cells were identified in biopsies of antibody mediated rejection in the peritubular capillaries where DSA bind the graft endothelial cells
Morvan MG, Lanier LL. NK cells and cancer: you can teach innate
cells new tricks. Nat Rev Cancer. (2016) 16:7–19
Paul S, Lal G. The molecular mechanism of natural killer cells function
and its importance in cancer immunotherapy. Front Immunol. (2017)
8:1124.
Yazdani S, Callemeyn J, Gazut S, Lerut E, de Loor H, Wevers M, et al. Natural
killer cell infiltration is discriminative for antibody-mediated rejection and predicts outcome after kidney transplantation. Kidney Int. (2019) 95:188–
98.
Excellent response and it is to the point.
You need to improve the style and structure of your writing.
Natural killer (NK) cells are effector lymphocytes originated from common lymphoid progenitors and represent 5–10% of circulating lymphocytes. NK cells represent one of the main cellular components of innate immunity
NK cells are different from cytotoxic T cells so they dont not require antigen exposure to mediate their effect , they are named for this natural killing cells .
They mediate immune responses against intracellular pathogens, so NK cells mainly produce cytokines including IFN-y, TNFa, and GMCSF which facilitate the activation of T cells, dendritic cells, macrophages, and neutrophils to enhance adaptive immune system
NK cell receptor repertoire is highly complex in human. And can express specific stimulatory and inhibitory receptors for various other ligands present on the surface of the target cells and the balance of inhibitory and stimulatory signals received by a NK cell determines the outcome of its interactions with target cells.
Normal cells are protected from NK cell killing since stimulatory receptors signals are balanced by inhibitory receptors signals coming from the interaction with the self-molecules of the MHC class I complex.
Mechanism of activation include
1-Direct lysis
2-Antibody-dependent cellular cytotoxicity (ADCC).
another essential feature of NK cell, is the production of pro-inflammatory or immunosuppressive cytokines .and the APC like dendritic cells can enforce the Cytolytic activity of the of NKC through the production of critical cytokines such as IL15, 12, 23, 27, and 18.
Recent studies in human found that subsets of NKC like NK CD56dim and CD56bright cells were increased in fibrotic renal tissue, but only CD56bright correlated significantly with loss of kidney function through the production of pro-inflammatory cytokines and IFN-g, that can play an important role in fibrotic process and in the progression of kidney injury.
NK Cell Involvement in Acute and Chronic Allograft Rejection
NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection. NK cells can also influence maturation of the APC like dendritic cells and lead to subsequent activation of T cells, Immunohistochemical characterization of graft infiltrating of CD56+ and CD57+ cells expression within the interstitial compartment, associated with interstitial inflammation and tubulitis which characterized the acute cellular rejection. NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR, where DSA bind the graft endothelial cells. DSA can interact with FcγRIII present on NK cells inducing an ADCC against the graft lead to endothelial cell injury. NK cells have been identified in the peri-tubular
Transplant tolerance.
Activated NK cells can directly kill donor-derived dendritic cells, thus promoting transplant tolerance. In mice tolerant models, NK cells can also produce high levels of IL10 thus showing tolerogenic ability. Both NK cells and Tregs might also influence each other by a mutual antagonism or by a temporary definition of their contribution in the induction of transplant tolerance.
Immunosuppressive drugs might modulate the phenotype of NK cells that can keep their ability to respond to stimulation. Moreover, immunosuppression can reduce the number of NK cells after transplantation, so Monitoring NK cell numbers and functions in transplanted patients under specific immunosuppressive regiments is important predict the onset of infections and neoplasia.
they are considered as attractive target for cancer immunotherapy becuase of thier ablity to kill tumour cells .
REFERNCES:
1-Halloran PF. T cell-mediated rejection of kidney transplants: a personal viewpoint. Am J Transplant. (2010) 10:1126–34. doi: 10.1111/j.1600-6143.2010.03053.
2- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24. doi: 10.4049/jimmunol.173.6.3716
PubMed Abstract | CrossRef Full Text | Google Scholar
3- 59. Dos Santos DC, Saraiva Camara NO, David DSR, Malheiros DMAC. Expression patterns of CD56+ and CD16+ cells in renal transplant biopsies with acute rejection: associations with microcirculation injuries and graft survival. Nephrology. (2017) 22:993–1001. doi: 10.1111/nep.12897
PubMed Abstract | CrossRef Full Text | Google Scholar.
4 The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation
-Front. Immunol., 23 July 2020 | https://doi.org/10.3389/fimmu.2020.01454
Thank you Dr. Saja
Excellent response
You raised the bar for all other candidates
Dear All
Does NK cells needs stimulation by antigen?
Does NK cells needs complement to exert its damaging effect?
If it is involved in Acute Antibody Mediated Rejection, do expect C4d staining to be positive?
NK cells dose not need antigen to stimulate their effect , thats why called natural killers they are different from cytoxic T cells as the later need priming by APCs they act by direct lysis effect and antibody dependent cell cytoxtoxicity ADCC .
the do involved in both ACR and ABMR
NK CELLS don’t need antigen stimulation hence the name natural and also they don’t need complement
no antigen needed for its stimulation, no complement needed for its damage.
no positive c4d stain if it is involved in AMR
NK cells are natural cytotoxic cells. They do not require any antigen exposure. Complement is not involved in their mechanism for graft rejection, hence C4d staining would be negative
NK cells does not need stimulation by antigen to exert their effect, also no complement activation is needed, it involves in both ABMR and T cell mediated rejection pathology ,, C4d is negative as there is no complement involvement
1-No they doesn’t stimulate by antigen
2-Yes they use complementary receptors
3-yes as the complement pathway is involved in their activation I expect the C4d will be positive
NK cells are a part of natural immunity. Deficiency or absence of MHC-class I may lead to activation of NK calls so there is no need to antigen for stimulation, and after activation, NK cells kill their target cells by secreting granzyme, perforin and INFγ and differentiate to memory cells. They don’t need to complement for activation and therefore C4d staining will not be positive after acute rejection.
NK cells along with macrophages, neutrophils, cytokines, certain cellular receptors, and complement system are part of natural or innate immunity and belong to the family of innate lymphoid cells (ILCs).
Human NK cells normally constitute 5-15% of human peripheral blood lymphocytes.
NK cells are lymphoid cells with unique features that do not carry BCRs and TCRs but express activating and inhibitory receptors including TLR2, 3, 4, 5, 7, and 8, and respond to the respective TLR ligands directly. Activating receptors play role in infection and inflammatory states by recognition of ligands on different cell types while inhibitory receptors bind self MHC class I molecules.
Stimulation of NK cells occurs once balance is in favor of activating signals. Indeed, the inhibitory receptors on NK cells are counterbalanced by activating receptors that recognize stress ligands expressed on the cell surface in response to intracellular DNA damage. NK cells distinguish and avoid healthy host cells through receptors that recognize MHC class I molecules expressed on all normal healthy cells. Binding of these receptors inhibits NK cell-mediated lysis, whereas deficiency or absence of MHC I leads to activation of the process of target attack and cell lysis.
Since allograft tissue expresses non-self MHC molecules, they do not engage inhibitory receptors on donor NK cells and so lead to NK cells activation. Thus, NK cells interestingly respond to missing self. On the other hand, NK cells infiltrating in to allograft can be activated by binding of alloantibodies in the graft to FcRs on NK cells. Once activated, NK cells kill their target cells by secreting granzyme, perforin and INFγ and differentiate to memory cells.
Another role of NK cells in allograft rejection is in the context of viral infections (especially herpes virus infections) that infected cells, because of diminished expression of MHC-class I and increased expression of activating ligands, are rapidly detected by NK cells and are killed.
(Traditionally, NK cells are considered cells of the innate immune response; however, there is accumulating evidence that at least some subsets respond to certain antigens in a manner that has the hallmarks of adaptive immunity.
The first evidence of this came from observations that mice deficient in T cells and B cells acquire antigen-specific immunological memory to hapten-based contact sensitizers that is mediated by a subset of primed, hepatic NK cells. Subsequent work has demonstrated that NK cells also acquire long-lived memory of diverse viral antigens.)
Paust S, von Andrian UH. Natural killer cell memory. Nat Immunol 2011
Nikzad R, Angelo LS, Aviles-Padilla K, et al. Human natural killer cells mediate adaptive immunity to viral antigens. Sci Immunol 2019
(In recent years, it has been appreciated how infection with human cytomegalovirus (HCMV) can shape the NK cell receptor repertoire. This HCMV-induced NK cell subset, interacting with self-HLA class I molecules. In addition, these NK cells can display some hallmarks of adaptive immunity, such as, enhanced effector function, longevity, clonal expansion as well as given epigenetic modifications, including epigenetic remodeling at the IFNG locus, and decreased expression of certain signaling molecules such as the adaptor protein FcRγ. HCMV infection also contributes to age associated changes in NK cells.
Similar to HCMV infection, Epstein-Barr virus (EBV) infection may change the composition of NK cells.
Natural killer cells may display alloreactive potential in case of mismatch between recipient inhibitory KIRs and graft HLA class I molecules in the context of solid organ transplantation including kidney transplantation. In this context, several lines of evidence support that “adaptive” NK cells may contribute to control viral infection in kidney transplant recipients. On the other hand, increasing evidence supports that alloantibody-mediated NK cell activation via Fc.RIIIA (CD16) may contribute to rejection in kidney transplant recipients.
Importantly, in addition to NK cells, ILCs may also represent important players in the early phases after transplantation.)
Marcenaro E, Notarangelo LD, Orange JS, Vivier E. Editorial: NK Cell Subsets in Health and Disease: New Developments. Front Immunol 2017
Natural killer cells are effector lymphocyte and they represent 5% to 10% of circulating lymphocytes
they are one of the main cellular component of the innate immunity , they are natural cytotoxic , they play a role against intracellular pathogens as well as they have a role in many inflammatory diseases through production of cytokines.
mechanism of their action by direct lysis or antibody dependent cellular cytotoxicity
( ADCC)
Natural killer cells in transplantation
NK cells have a role in acute and chronic T cell mediated rejection / antibody mediated rejection
Antibody mediated rejection through the expression of CD16. This function can be triggered by anti-HLA antibodies, in particular by DSAs . where DSA bind the graft endothelial cells. Once bound to endothelial cells DSA can interact with FcγRIII present on NK cells inducing an ADCC against the graft.. NK cells have been identified in the peri-tubular capillaries of the biopsies of patients ABMR.
T cell mediated rejection through the secretion of pro-inflammatory molecules such as IFN-g , which increase the recruitment of alloreactive T cells and up-regulate HLA alloantigens (MHC I and II) on graft target cells, making them more susceptible to cytotoxic killing .patients with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, both characteristics of T cell-mediated rejection.
NK Cells and Transplant Tolerance
Natural killer cell can cause tolerance after their activation by inflammatory environment mediated by the cytokines produced by dendritic cells and T cells . These activated NK cells can kill donor-derived dendritic cells through direct lysis , thus inhibiting the immune response and promoting induction of tolerance .
NK cells and immunosuppressive drugs
Immunosuppressive drugs have limited effect on the activity of NK cells in transplant recipients .
From a therapeutic point of view, and new treatments targeted to activated NK cells and/or their effector functions should be explored.
Immunosuppression may influence the number of NK cells over time. In patients treated with cyclosporine compared to patients treated with tacrolimus.
Routine monitoring NK cell number in the context of immunosuppressive regimens
in transplanted patients is important to control and predict the onset of infections and neoplasia . NK cells, indeed, play an important role in cancer defense, and the incidence of cancer is deeply increased after transplantation and playing important role in protecting against human Cytomegalovirus infection.
References
Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol. 2020;11:1454.
Excellent Alyaa
NK cells represent are one of the main cellular components of innate immunity(5–10% of circulating lymphocytes).
§ They are named “natural killers” because they do not require activation to kill cells that are missing “self” markers of MHC class I. NK cells can be identified by the presence of CD56 and the absence of CD3
§ Theses cytotoxic cells are analogous to the cytotoxic T cells in the adaptive immune system . However, they do not require antigen exposure to mediate their effect.
§ The interaction of NK cells with target cell to define their fate is determined by a balance between stimulatory and inhibitory receptors. Inhibitory receptors (KIR) recognize cognate MHC I, and this ‘switches off’ NK cell, preventing it from killing.
NK Subsets: NK cells can be classified as CD56bright or CD56dim.CD56bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines, whereas, CD56dim NK cells are always CD16 positive(key for ADCC)
Function of NK cells:
1. The NK cells has a cytolytic effector activity through the production of proteins as perforin and proteases called granzyme
2. Antibody-dependent cell-mediated cytotoxicity (ADCC):Antibodies that bind to antigens can be recognized by CD16 receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis
.
3. NK cells secrete interferon gamma and Tumor necrosis factor alpha .IFNγ activates macrophages for phagocytosis and lysis and TNFα acts to promote direct NK tumor cell killing and controlling viral infections(1).
NK cells in Renal transplantation:
NK cells promote allograft injury but also play a role in the priming of allograft tolerance
Role of NK cells in Acute and Chronic Allograft Rejection:
· NK cells can influence maturation of dendritic cells and the subsequent activation of T cells.
· NK cells are an early source of IFN-g, which drive a Th1-type immune response.
· NK cells can interact directly with CD4+ T lymphocytes ;increasing their reactivity, and induce acute rejection mechanisms.
· NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
· Turner et al (2) found that in antibody-mediated rejection, NK cells is demonstrated in the transplant renal biopsy (peri-tubular capillaries) whereas T cell-mediated rejection was confirmed by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis. (3).
· Data signifies the importance of CD56dim cells activation in featuring ABMR, where they can guide vascular damage but CD56bright NK cells can instead play a specific role in TCMR(4).
· The different role of NK cells in ABMR compared to the TCMR was studied kidney graft biopsies that revealed high levels of NK cells in early T cell-mediated rejection while late biopsies showed increased number of NK cell in patients with antibody-mediated rejection, microvascular inflammation, and DSA(5).
The role of NK Cells in Transplant Tolerance:
The direct correlation between NK cells and Tregs in inducing tolerance is currently controversial It is thought NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .It is therefore possible that NK cells do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response(6).
The effect of immunosuppression on NK cells:
· Immunosuppressive drugs can modulate the phenotype of NK cells following renal transplantation, so, NK cells can act as sensors for immunosuppression .
· Current immunosuppressive regimens are unable to down-regulate the function of NK cells and thus new treatments targeted to activated NK cells should be explored. (1).
References:
1)The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Paola Pontrelli et al,. Front. Immunol., 23 July 2020
2) Natural killer cells in kidney health and disease Turner JE, Rickassel C, Healy H, Kassianos AJ. Front Immunol. (2019)
3) Compartment-specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection. Dos Santos DC, Campos EF, Saraiva Câmara NO, David DS, Malheiros DM. Transpl Int. (2016) 29:443–52
4) Specialized roles of human natural killer cell subsets in kidney transplant rejection. Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Front Immunol. (2019)
5) Interpreting F NK cell transcripts versus T cell transcripts in renal transplant biopsies. Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran P. Am J Transplant. (2012) 12:1180–91
6)The varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. Beilke JN, Grill RG. Frontiers in nephrology: J Am Soc Nephrol. (2007)
Excellent Ahmed
§ NK cells represent are one of the main cellular components of innate immunity(5–10% of circulating lymphocytes).
§ They are named “natural killers” because they do not require activation to kill cells that are missing “self” markers of MHC class I. NK cells can be identified by the presence of CD56 and the absence of CD3
§ Theses cytotoxic cells are analogous to the cytotoxic T cells in the adaptive immune response. However, they do not require antigen exposure to mediate their effect.
§ The interaction of NK cells with target cell to define their fate is determined by a balance between stimulatory and inhibitory receptors. Inhibitory receptors (KIR) recognize cognate MHC I, and this ‘switches off’ NK cell, preventing it from killing.
NK Subsets: NK cells can be classified as CD56bright or CD56dim.CD56bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines, whereas, CD56dim NK cells are always CD16 positive(key for ADCC)
Function of NK cells:
1. The NK cells has a cytolytic effector activity through the production of proteins as perforin and proteases called granzyme
2. Antibody-dependent cell-mediated cytotoxicity (ADCC):Antibodies that bind to antigens can be recognized by CD16 receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis.
3. NK cells secrete IFNγ and TNFα.IFNγ activates macrophages for phagocytosis and lysis and TNFα acts to promote direct NK tumor cell killing and controlling viral infections(1).
NK cells in Renal transplantation:
NK cells promote allograft injury but also play a role in the priming of allograft tolerance
Role of NK cells in Acute and Chronic Allograft Rejection:
· NK cells can influence maturation of dendritic cells and the subsequent activation of T cells.
· NK cells are an early source of IFN-g, which drive a Th1-type immune response.
· NK cells can interact directly with CD4+ T lymphocytes ;increasing their reactivity, and induce acute rejection mechanisms.
· NK cells can contribute in different ways to the pathogenesis of both acute and chronic T cell-mediated and antibody-mediated rejection.
· Turner et al (2) found that in antibody-mediated rejection, NK cells is demonstrated in the transplant renal biopsy (peri-tubular capillaries) whereas T cell-mediated rejection was confirmed by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis. (3).
· Data signifies the importance of CD56dim cells activation in featuring ABMR, where they can guide vascular damage but CD56bright NK cells can instead play a specific role in TCMR(4).
· The different role of NK cells in ABMR compared to the TCMR was studied kidney graft biopsies that revealed high levels of NK cells in early T cell-mediated rejection while late biopsies showed increased number of NK cell in patients with antibody-mediated rejection, microvascular inflammation, and DSA(5).
The role of NK Cells in Transplant Tolerance:
The direct correlation between NK cells and Tregs in inducing tolerance is currently controversial It is thought NK cells would induce tolerance in the first 3 weeks after transplantation by blocking dendritic cells and/or T cells that could start rejecting the graft, while Tregs, by maturing later, would maintain the long-term tolerance toward the graft .It is therefore possible that NK cells do not induce tolerance but simply allow the survival of the graft while the recipient develop a regulatory response(6).
The effect of immunosuppression on NK cells:
· Immunosuppressive drugs can modulate the phenotype of NK cells following renal transplantation, so, NK cells can act as sensors for immunosuppression .
· Current immunosuppressive regimens are unable to down-regulate the function of NK cells and thus new treatments targeted to activated NK cells should be explored. (1).
References:
1)The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Paola Pontrelli, Federica Rascio, Giuseppe Castellano, Giuseppe Grandaliano, Loreto Gesualdo and Giovanni Stallone.. Front. Immunol., 23 July 2020
2) Natural killer cells in kidney health and disease Turner JE, Rickassel C, Healy H, Kassianos AJ. Front Immunol. (2019)
3) Compartment-specific expression of natural killer cell markers in renal transplantation: immune profile in acute rejection. Dos Santos DC, Campos EF, Saraiva Câmara NO, David DS, Malheiros DM. Transpl Int. (2016) 29:443–52
4) Specialized roles of human natural killer cell subsets in kidney transplant rejection. Kildey K, Francis RS, Hultin S, Harfield M, Giuliani K, Law BMP, et al. Front Immunol. (2019)
5) Interpreting F NK cell transcripts versus T cell transcripts in renal transplant biopsies. Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran P. Am J Transplant. (2012) 12:1180–91
6)The varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. Beilke JN, Grill RG. Frontiers in nephrology: J Am Soc Nephrol. (2007)
Excellent Ahmed
Natural Killer (NK) cells are effector lymphocytes deriving from common lymphoid progenitors and represent 5-10% of circulating lymphocytes and have a different subset. They are natural cytotoxic cells, but unlike cytotoxic T lymphocytes, they don’t require antigen exposure to mediate their effect.
They achieve their cytolytic effector activity through 2 main mechanisms of action:
1. Direct lysis
2. Antibody-dependent cellular cytotoxicity(ADCC)
-In both mechanisms, the lytic function of NK cells depends upon cytolytic molecules, mainly granzyme and perforin, and their activation leads to the production of several inflammatory cytokines.
-NK cells link between innate and adaptive immune systems and protect against excessive immune response to antigens.
– NK influence the maturation of dendritic cells and subsequent activation of T cell also NK can interact directly with CD4 T lymphocytes, increasing their reactivity and can induce acute rejection.
-NK cells are involved in different ways in acute and chronic T-cell mediated rejection and antibody-mediated rejection.
-CD56dim/CD16 NK cells represent the main NK subset involved in the pathogenesis of ABR by ADCC on the target cell into the graft.
-NK cells can kill donor-derived dendritic cells through direct lysis that leads to promote tolerance that can be maintained with the production of IL-10 by NK cells.
-Immunosuppressive drugs might modulate the phenotype of NK cells after kidney transplantation and influence the number of NK over time.
-Monitoring NK cells number in the transplanted patient can predict the onset of infection and neoplasia.
Referrence:
Paola Pontrelli, Federica Rascio, Giuseppe Castellano, Giuseppe Grandaliano, Loreto Gesualdoand Giovanni Stallone. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol., 23 July 2020
Well done
Description of NK cells
1. NK cells are cytotoxic lymphocytes that are secreted from bone marrow
2. Located mainly in the peripheral circulation with minority in organs
3. Constitutes 5-10% of total lymphocytes in peripheral blood
4. Responsible for innate and not adaptive immunity
5. Do not have antigen specific receptors like TCR for T cells and IG for B cells but have activating and inhibitory cell surface receptors (1)
Activation and inhibition of NK cells
⦁ Inhibited by binding of inhibitory cell surface receptors (one of them is KIRs) to MHC antigens class I which is present on the surface of the host healthy cells (1)
⦁ Activated by recognizing damaged cells (infected or malignant cells ) with no MHC class I antigens on its surface since these cells downregulate MHC class I molecules
⦁ So damaged cells are killed while healthy cells are avoided
⦁ NK cell become attached to the target cell either by direct interaction between ligands on target cells and conjugate receptors on NK cells without the need for adaptive immune response (spontaneous cytotoxicity) or through attachment to Fc portion of IgG attached to target cell (antibody-dependent cellular cytotoxicity)
Effect of activated NK cells
⦁ Cytotoxic killing of target cell occur by secreting granules that disrupt target cell membrane and induce apoptosis (2).
⦁ NK cells increase the activity of CD4+ T lymphocytes through direct interaction (3).
⦁ NK1 cells secrete interferon (IFN)-gamma that activates macrophages, and stimulate CD4 T helper 1.
⦁ NK2 cells produce IL-5 and IL-13 that induce humoral immunity and may play a rule in bronchial asthma and atopic diseases.
⦁ NK cells produce IL 10 that lead to development of regulatory dendritic cells leading to tolerance (4)
Clinical significance of NK cells in renal transplantation
1. Play an important rule in acute and chronic TCMR, ABMR (5) through either antibody- dependent cellular cytotoxicity , activation of CD4 T helper 1 response, promotion of migration of immune cells to the graft especially dendritic cells or through direct infiltration of the graft by NK cells.
2. Play an important rule in clinical tolerance
3. Immunosuppression decrease NK cells function and number leading to increase in the incidence of malignancy and infection.
4. Immunosenecence reported in elderly population occur in part due to decrease in number and function of NK cells (6)
REFERANCES
1- Paust S, Senman B, von Andrian UH. Adaptive immune responses mediated by natural killer cells. Immunol Rev 2010; 235:286
2- Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2:735.
3- Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human, cells NK, and CD4, T cells via OX40-OX40 ligand interactions. J Immunol. (2004) 173:3716–24
4- Jiang X, Kojo S, Harada M, Ohkohchi N, Taniguchi M, Seino KI. Mechanism of NKTcell-mediated transplant tolerance. Am J Transplant. (2007) 7:1482–90.
5- Beilke JN, Grill RG. Frontiers in nephrology: the varied faces of natural killer cells in transplantation—contributions to both allograft immunity and tolerance. J Am Soc Nephrol. (2007) 18:2262–7
6- Tobin LM, Mavinkurve M, Carolan E, et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2017; 2.
Well structured answer as usual. Very impressive
NK cells are natural cytotoxic cells, but don’t need antigen exposure to mediate immune response ( unlike cytotoxic T cells). It comprises 5-10% of total circulating lymphocytes. It considered as one of innate immunity component. Its immune response usually against intracellular pathogens but also had another role through production of different cytokines. Nk cells accomplish cytolytic activity through:
Another feature of NK cells is production of pro inflammatory & immunosuppressive cytokines which is different from cytotoxic granules secretion.
NK cells is the main regulator of immune response & it cross-talk between innate & adaptive immunity. Nk cells activated by various soluble factors ( IL5, type I INF, IL12, IL18) so it can induce maturation & stimulation of dendritic cells, macrophages & T cells
Nk cells role in solid organ transplant still controversial , but it may promot graft injury. There is some evidence that NK cells may play major role in priming graft tolerance. Also it found that the number & phenotypes of NK cells are different in post transplant than in pre transplant, so it may play a role in graft out come.
NK cells can directly interact with CD4 T cells & increase their activity so increase the risk of acute rejection. Yagisawa et al found that in mice renal transplant the acute rejection is caused by presence of both NK cells & DSA, & in absence of NK cells activation & presence of DSA alone can not induce acute AMR, but it still lead to late graft failure. NK cells have a role in T cell mediated rejection.
Reference:
Pontrelli P., Rascio F., Castellano G., et al. The Role of Natural Killers in the Immune Response in Kidney Transplantation. Front Immune, 2020.
Yes, NK cells are natural cytotoxic cells, but don’t need antigen exposure to mediate immune response (unlike cytotoxic T cells) and also do nor require complement to exert its damaging effect.
Well done
Natural killer cells is a population of lymphocytes that represent one of the main cellular components of innate immunity along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. NK represent 5–10% of circulating lymphocytes. In addition to their role in anti-viral and anti-tumor defense, they have impact in alloimmune response in kidney transplant. NK cells lack TCR or BCR but they have complementary activating and inhibiting receptors. Growing evidence is suggesting a major role of NK cells in the pathogenesis of immune-mediated allograft damage. Specific NK cell subsets are associated with tolerance in kidney transplant recipients. On the other side, activated NK cells are associated with chronic AMR and graft loss.
The NK cells accomplish their cytolytic effector activity through two main mechanisms of action:
1. Direct lysis of graft cell. The recognition of HLA class I molecules by inhibitory receptors (KIRs: Killer cell immunoglobulin-like receptors) on NK cells inhibits their cytotoxic activity and maintains the recognition of self. In the case of “missing self ” instead, the absence of class I HLA molecules on target cells prevents inhibitory signals and leading to of secreting same molecules as the cytotoxic T lymphocytes and subsequent killing/lysing the target cell.
2. Antibody-dependent cellular cytotoxicity. The interaction between the Fc receptor FcγRIII (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells induces the lysis of these cells.
3- T NK cells are also implicated in IFN-g release, which drives a Th1-type immune response. NK cells can interact directly with CD4+ T lymphocytes, increasing their activity in inducing ABMR.
4- NK cells can also influence maturation of dendritic cells into APC and the subsequent activation of cells. Immuno-histochemical staining of kidney graft with acute T cell-mediated rejection are characterized by a higher number of CD56+ and CD57+ cells within the interstitial compartment, associated with interstitial inflammation and tubulitis, that are characteristics of T cell-mediated rejection.
5-NK cells have potent immunoregulatory properties that influence tolerance induction. The maintenance of transplant tolerance could be also associated with the production of IL-10 by NK cells. Upon stimulation with glycolipids, NK cells produce high levels of IL-10 that can promote the development of regulatory dendritic cells.
References:
-Handbook of kidney transplantation sixth edition
-doi: 10.3389/fimmu.2020.01454
-doi: 10.3389/fimmu.2019.01877
-doi: 10.5772/intechopen.78804
-doi: 10.4049/jimmunol.173.6.3716
Excellent summary. It would be better in your own words. It is a good training and improves your writing skills.
function of NK
Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells, coming from a common progenitor. However, NK cells are classified as group I Innate Lymphocytes (ILCs) and respond quickly to a wide variety of pathological challenges. NK cells are best known for killing virally infected cells and detecting and controlling early signs of cancer.
Role of NK Cells in Kidney Transplantation
NK cells have a key role in the pathogenesis of immune-mediated graft damage in kidney transplantation.
1-Specific NK cell subsets are associated with operational tolerance in kidney transplant patients.
2-On the other side, alloreactive NK cells are associated with chronic antibody-mediated rejection and graft loss.
3-In addition, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased alloimmune response and, eventually, to chronic graft rejection.
4- Activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection.
Immunosuppression effects on NK Cell Behaviour
Immunosuppressive drugs might modulate the phenotype of NK cells after kidney transplantation, thus suggesting that NK cells can serve as sensors for immunosuppression and can be considered for personalized immunosuppression therapy adjustment.
immunosuppression may influence the number of NK cells over time. In patients treated with cyclosporine compared to patients treated with tacrolimus, the number of NK cells as well as the ratio CD56dim/CD56bright is lower and the cytotoxic activity is reduced 1 year after transplantation.
It will be useful in the future to routinely monitor and evaluate NK cell function in the context of specific algorithms to personalize immunosuppressive regimens.
Moreover, Monitoring NK cell number and especially NK cell function in transplanted patients is also important to control and predict the onset of infections and neoplasia.
References
98. Neudoerfl C, Mueller BJ, Blume C, Daemen K, Stevanovic-Meyer M, Keil J, et al. The Peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs. Front Immunol. (2013) 4:46. doi: 10.3389/fimmu.2013.00046
99. Vacher-Coponat H, Brunet C, Moal V, Loundou A, Bonnet E, Lyonnet L, et al. Tacrolimus/mycophenolate mofetil improved natural killer lymphocyte reconstitution one year after kidney transplant by reference to cyclosporine/azathioprine. Transplantation. (2006) 82:558–66. doi: 10.1097/01.tp.0000229390.01369.4a
100. Stallone G, Infante B, Grandaliano G. Management and prevention of post-transplant malignancies in kidney transplant recipients. Clin Kidney J. (2015) 8:637–44. doi: 10.1093/ckj/sfv054
Thanks Dr Mohamed
There is an obvious copy and pasting in your reply.
thank you Dr.Ahmed ,I will avoid that in future.
NK cells are effector lymphocytes derived from common lymphoid progenitors and represent 5-10% of circulating lymphocytes. They are natural cytotoxic( do not require antigen exposure to exert their effect).
The role of NK cells in transplantation:
References:
Well done
Natural Killer cells role in transplantation:
1- Regarding acute rejection: upon stimulations, NK cells secrete different cytokines e.g. IFN gamma which in some studies was found to cause arterial stenosis with resultants graft rejection/(1) In addition, IFN gamma may lead to activation of T cells as well.
2- NK can recognize certain ligands which upon activation may lead to graft rejection.
3- on the other hand, NK cells may help in tolerance of transplanted organ as NK help in elimination of donor dendric cells so they helped in prevention of activation of T cells and rejection process (2)
4 – the exact mechanism of NK cells role in transplantation is still not clearly under stood. also, there is no coloration between NK cells activation and rejection.(3)
References:
Multiple roles of NK cells in kidney transplantation:
1- NK cells that present CD56/CD16 can interact with DSA present on graft endothelial cells and induce antibody mediated rejection.
2- Also has a role in cellular rejection by release of interferon gamma (pro inflammatory mediator) from NK CD56.
3- Transplant tolerance, it has a positive role in transplant tolerance as it kills dendritc cells of donor (APC), also can release IL-10 which possess tolerogenic character, also antagonistic effect between Treg and NK cells is evident to induce tolerance.
4- Immunosuppressive drugs like CNI and mTor inhibitors can modify its function and decrease its number.
5- Still NK cells have anti infectious and anti-tumor function.
Paola Pontrelli, Federica Rascio, Giuseppe Castellano, Giuseppe Grandaliano, Loreto Gesualdo. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front. Immunol., 23 July 2020.
Natural killer (NK) cells are effector lymphocytes that develop from common lymphoid progenitors, accounting for 5–10% of all circulating lymphocytes. NK cells are natural cytotoxic cells that do not require antigen exposure to exert their effect, unlike cytotoxic T lymphocytes.
Along with mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells, NK cells are one of the most important biological components of innate immunity.
They exert immune responses against intracellular pathogens.
The NK cells accomplish their cytolytic effector activity by:
1. Direct lysis. The recognition of HLA class I molecules by inhibitory receptors on NK cells inhibits their cytotoxic activity. Thus, rather than the presence it’s the absence of class I HLA molecules on target cells leads to the cytotoxicity of NK cells.
2. Antibody-dependent cellular cytotoxicity (ADCC). The interaction between the (CD16) expressed on NK cells and the Fc fragment of an antibody recognizing foreign antigens on target cells (e.g., infected cells) induces the lysis of these cells.
The multiple role of NK cells in kidney transplantation.
(A) Graft rejection=
CD56dim/CD16 NK cells can promote ADCC against the graft by interacting with DSA bound to the graft endothelial cells, thus driving antibody-mediated rejection (ABMR). CD56bright NK cells can instead play a specific role in cell-mediated rejection (TCMR) through the secretion of pro-inflammatory molecules such as IFN-g.
(B) Transplant tolerance=
activated NK cells can directly kill donor-derived dendritic cells, thus promoting transplant tolerance. NK cells can also produce high levels of IL10 thus showing tolerogenic ability. NK cells and T regs might also influence each other by a mutual antagonism or by a temporary definition of their contribution in the induction of transplant tolerance.
(C) Immunosuppression=
Immunosuppressive drugs might modulate the phenotype of NK cells that can retain their ability to respond to stimulation. Moreover, immunosuppression can reduce the number of NK cells after kidney transplantation.
The Role of Natural Killer Cells in the Immune Response in Kidney TransplantationPaola Pontrelli et al