-It may be due to upregulation during inflammation, in response to transplantation, or when proteins are exposed to the immune system during injury. It is thought that the intragraft microenvironment or rejection may break humoral tolerance to autoantigens .
Public epitope and cross-reactive groups (CREGs) which sharing many HLA antigens which can cross reactivities by single anti HLA antibody which explain non-DSA antibody appearance.
The antibody attachment site on the HLA antigen surface is called the epitope. Single HLA antigen may have different epitopes, some of which may be “private” epitopes which are unique to this specific HLA antigen. On the other hand, some epitopes are “public” epitopes that may be present on several distinct HLA antigens (1).
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody. It is the traditional (serologic) expression of the modern (molecular-based) public epitopes (1).
Each HLA Ag have on there surface many epitopes which are the AB attachments site these epitopes can be shared between one or more HLA Ag (public epitopes) and some are private to specific HLA Ag (private epitopes).
CREGS mean that different HLA Ags can react with single antibody.
A public epitope is antigen-antibody binding site shared by more than 1 antigen.
CREG (Cross reactive group): It is a group of antigens cross reactive with a single antibody. So all the members of CREG will have same epitope, which can be called a public epitope.
public epitope which shared by another antigens and there is private epitope which not shared by another.
The group of antigens that cross react with the single antibody called CREGs
Public epitopes ; if one antibody bind more than one similar eiptopes, they are called public epitopes. If the one antibody binds only one epitope without binding other epitopes , the eiptope is called private epitope. CREGs refers to group of antigens that have common antibody binding site.
public epitopes are an antigen-antibody binding site that can be shared by more than one antigen.
CREGs are groups of antigens that cross-react with a single antibody
epitop is the site of HLA antigens were the DSAs bound, usually represnted by certain sequence of amino acids called eplets against which the donor is mounting an antibody reaction, when thses eplets are shared between more than one HLA antigens then the same anti HLA antibody will react with different HLA antigen, some of them are non Donor soecific HLA antibodies (third party), that is why its called shared epitop.
CREGs (cross reacting groups) are set of different HLA antigens reacting with a single anti HLA antibody basically because they are sharing the same epitops.
Nearly similar things.. Pulblic epitopes found in in some HLa antigens are structural similar so one who have antibody to one epitope, He well have or develop antibodies to the other HLA antigen. fore example: patients sensitized to HLA A2 probably well develop antigens to : A23, A24, A68, A69, B57 &B58
Antibodies that can be detected in transplantation and may impact graft survival are classified into :
Antibodies can be :
HLA DSA ( HLA antibodies in recipient against donor )
or
HLA non DSA also named third party anti-HLA antibodies (HLA antibodies not against the donor )
Or
Non HLA as Anti-endothelial cell antibodies , Angiotesin II type1 receptor(ATR1)
Explanation of NDSA
exposure to sensitizing event as pregnancy , blood transfusion or infection.
may be due to
1- non specific response due to formation of polyclonal Ab in response to single Ag
2- Ab formation against shared epitopes between DSA and NDSA HLA molecules or against CREG
3- Cross reactivity of common epitopes or antigenically related HLA molecules and an infectious agent that may also trigger robust activation of memory cells .
4- increase expression of non self self HLA Ag on the recipient cells as the level of NDSA commonly increase during rejection episodes in association with rising DSA levels .
this leads to poor graft outcomes and increased risk of AMR
Public epitopes it is HLA binding site called epitopes with functional amino acid called epilets when group of epitopes have similarity to share with different HLA antigens and react with single Ab called puplic .
GREGs groups of antigens react with single Ab.
The public epitope is shared by more than one antigen while CREGs is a group of antigens which react with same antibody . So all antigens in CREGs will have same epitope and it will called public epitope
Public epitopes refer to epitopes that are shared by more than one HLA antigen. HLA antibodies will show reactivity with the antigen that contains the public epitope.
Cross reactive groups (CREGs) are a group of antigens that share a public epitope. This is seen by a specific antibody that reacts with all of them.
Antibodies bind to HLA antigens on target epitopes,Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross-reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes.
How do you explain the appearance of non-DSA
The appearance of non-DSA is due to sensitization event like DSA. because non-DSA for one recipient could be donor specific for another. So sensitization events like blood transfusion, pregnancies and re-transplant are common. Another trigger for non-DSA is immune response to vaccinations or viral illnesses like COVID19.
The renal transplant patients frequently have non-donor-specific HLA antibodies (NDSA),a negative crossmatch in a sensitized patient. Usually NDSA levels slowly fall in the first month after transplantation, but in another cases some patients the level of NDSA rise during the time of rejection with increase in the level of DSA. The appearance of NDSA could be due antibodies against shared(public) epitopes or due to immune upregulation secondary to bacterial, viral infections or some types of vaccinations (Generation of memory cells either T or B memory cells which just need very low activation stimulus (antigen stimulation) to activate their responses and unfraternally they are very resistant to conventional immunosuppression.
How do you explain the appearance of non-DSA?
——————————————————————-
Non-DSA can occur in a setting of a negative XM in asensitized patient.
Levels slowly fall in the 1st post-transplant month, & may initially rise during AR with increased synthesis of DSA. This is explained by antibodies binding with shared epitopes on DSA & Non-DSA; giving rise to apparently non-donor specific HLA sensitization, although the epitopes are indeed donor specific.
Alternatively it could be due to non-specific immune up-regulation.
after renal transplantation, there are antibodies formed in the recipient which may be non DSA (with negative cross match), or DSA (positive cross match), these non DSA can fall in the 1st month post transplant , or may increase and persist predispose to rejection through immunological upregulation response or increase DSA , shared epitopes between DSA and non DSA
so it may be a new way to know or predict rejection episodes in such patients
D Briggs, D Zehnder, R M Higgins. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications.
Contrib Nephrol. 2009;162:107-16.
non-donor specific antibodies refere to recipients specific allo -or autoantibodies with negative crossmatch and negative DSA in previously sensitized recipients ususally non-DSA fall immediatly in the first month post transplant but in some cases their expression increaseed or triggered during, acute ischemic injury (IRI) ,infections ( viral ),immunazation,blood group incompatiblity due to epitope sharing and crossreactivity with donor specific antigens or nondonor HLA antigens .
References:
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
4% of acute rejection episodes among transplant recipients are caused by NDSA. Presence of NDSA can predict poor graft survival especially in recipients didn’t receive induction or receive anti-IL-2 R, but patients who use induction with T cell depleting agent had better prognosis.
HLA loci had a wide polymorphic regions (>25,000 HLA alleles) . The different alleles can share epitopes with each others . Shared epitopes can cause alloimmunity by B cells epitopes(BE). HLA that shared BE called CREG, & antibodies against donor CREG (NDSA) associated with increased risk of early ABMR.
The development of post-transplant antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, recent studies provide compelling experimental and clinical findings demonstrating that antibodies directed against autoantigens contribute to the process of antibody-mediated acute and chronic rejection. Important areas for investigation remain understanding the mechanisms underlying the production of autoantibodies in the setting of organ transplantation. Ischaemia- reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ- derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production. Th17 cells are essential in the orchestrating autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promoteallograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non- HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.
immunity to non- HLA antigens also portends poorer long-term allograft outcome.
Non-HLA antibodies are classified into two main categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor, and antibodies that recognize self-antigens — autoantibodies. As the vasculature is at the interface of the recipient immune system and the transplanted organ, a substantial proportion of the non- HLA antibodies reported to mediate renal rejection recognize autoantigens expressed by endothelial cells.
despite generating autoantibodies following transplantation, the majority of patients did not experience rejection or graft dysfunction. This finding suggests that the pathogenicity of the autoantibodies is conditional upon other factors such as ligand expression, ischaemic injury and/or the state of inflammation within the microenvironment of the allograft. The expression of autoantigens on the endothelium can vary widely depending upon their anatomical location, vessel type and inflammatory milieu, which might pose challenges to ascribe clinical relevance to non-HLA autoantibodies.
NDSA Traditionally dismissed as a risk factor
Malheiro et al 2017 demonstrated that NDSA are associated with worse graft outcome if not received strong induction with ATG
Severova et al 2018 also confirmed the increased risk of AMR and graft dysfunction due to NDSA
Crossreactivity between public epitobs has a major role in the development of NDSA ,this decrease after one month post-transplantation but upregulated after any trigger like infection,immunization or blood transfusion.
Reference:
The importance of non-HLA antibodies in transplantation
Qiuheng Zhang and Elaine F. Reed
UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
1) Antibodies giving rise to false positive crossmatch – like autoantibodies.
2) Natural antibodies: in untransfused males, against cross-reactive epitopes found in microorganisms, ingested proteins and allergens.
3) Antibodies formed due to exposure to HLA not present in the current donor: levels may rise on immune upregulation or due to antigen-specific stimulation (if have cross-reactivity with the HLA on the donor – public epitope).
4) Antibodies formed by exposure to HLA present on the current donor having cross-reactivity with HLA specificities not on the current donor.
References: 1) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818. 2) Morales-Buenrostro LE, Terasaki PI, Marino-Vázquez LA, Lee JH, El-Awar N, Alberú J. “Natural” human leukocyte antigen antibodies found in nonalloimmunized healthy males. Transplantation. 2008 Oct 27;86(8):1111-5. doi: 10.1097/TP.0b013e318186d87b. PMID: 18946350.
after exposure to HLA antigens during pregnancy ,blood tx ,previous tx and previous immunization or infection >>> antibodies formed against public epitops and CREG
It could be due to antibodies binding to shared epitopes on non-donor-specific HLA, or due to non-specific immune upregulation. reference
Remuzzi G, Chiaramonte S, Perico N, Ronco C (eds) (eds): Humoral Immunity in Kidney Transplantation. Contrib Nephrol. Basel, Karger, 2009, vol 162, pp 107-116
When it comes to the formation of NDSA, crossreactivity across public epitopes plays a significant role. This decreases after one-month post-transplantation but is increased following any trigger such as infection, vaccination, or blood transfusion.
Antibodies giving rise to false positive crossmatch test.
Maybe autoreactive; may be positive in cellular crossmatch test but not found on solid-phase assays, not clinically relevant ‘Natural’ antibodies.
Have been described in untransfused males, clinical relevance uncertain. Antibodies generated by previous exposure to HLA specificities not present on the current donor.
May have no cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation.
May have cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
May have cross-reactivity with HLA specificities, not on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
Reference: Briggs D, Zehnder D, Higgins RM. Development of Non-Donor-Specific HLA Antibodies after Kidney Transplantation: Frequency and Clinical Implications. Contrib Nephrol. Basel, Karger, 2009, vol 162, pp 107–116.
Epitops are sites of HLA antigen recognized by the Anti HLA antibodies , this recognition depends on a certain amino acids sequence called eplets(which are the functional epitops) , each HLA molecule has many epitops. In some cases those eplets are shared between different HLA antigens and its called public epitops, leading to the cross reaction of same anti HLA antibody with different HLA antigens and some times it might cause a reaction with non Donor HLA antigen (non existing) called non Donor specific antibody non _DSAs, third party HLA Antibodies. Its lmportant and associated with poor allograft outcome in patients who did not receive ATG induction in the anti rejection protocol at time of transplantation.
Public epitopes may coincide at other HLA sites, explaining sensitization and rejection in patients undergoing solid organ transplants who supposedly had specific donors. One way to predict these situations is with Epitope Matching, mainly:
1. Sensitized patients to determine which antigens are acceptable or not
2. Retransplantation for better compatibility with the previous graft
3. Plan to minimize or suspend immunosuppression
NDSA may result from exposure to sensitizing event as pregnancy , blood transfusion or infection. The proposed underlying pathogenesis may be
1- Immune up regulation with non specific response secondary to formation of polyclonal Ab in response to single Ag
2- Ab formation against shared epitopes between DSA and NDSA HLA molecules or against CREG
3- Cross reactivity of common epitopes or antigenically related HLA molecules and an infectious agent that may also trigger robust activation of memory cells .
4- increase expression of non self self HLA Ag on the recipient cells as the level of NDSA commonly increase during rejection episodes in association with rising DSA levels .
Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
NDSA
-level slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA.
-This could be due to antibodies binding with shared epitopes on donor-specific and nondonor-specific HLA, or due to non-specific immune upregulation.
Antibodies giving rise to false positive crossmatch test
• May be autoreactive; may be positive in cellular crossmatch test but not found on solid phase assays, not clinically relevant
‘Natural’ antibodies
• Have been described in untransfused males, clinical relevance uncertain
Antibodies generated by previous exposure to HLA specificities not present on current donor
• May have no cross-reactivity with HLA specificities on current donor, levels may rise due to immune upregulation
• May have cross-reactivity with HLA specificities on current donor, levels may rise due to immune upregulation or to antigen-specific stimulation
Antibodies generated by exposure to HLA specificities present on current donor
• May have cross-reactivity with HLA specificities not on the current donor, levels may rise due to immune upregulation or to antigen-specific stimulation
Non-DSA (third party DSA) were traditionally dismissed as a risk factor for allograft failure, Malheiro et al (2017) demonstrated that Non-DSA were associated with worse graft outcome if not received strong induction with ATG>> their appearance mostly explained due to the presence of shared epitopes within the HLA Ags
Actually, HLA Abs are directed against private specifications such as HLA-A1 which recognize an epitope that is unique to a particular HLA or a limited family of closely related alleles., Abs directed public specifications (public epitopes) like Bw6, which are shared by more than one HLA molecule are responsible for cross reactivity observed in HLA allo-antiserum the so called CREG.
Public Epitope and Cross-Reactive Groups (CREGS)
Shared by many HLA antigens and can cause cross reactivities by a single anti HLA antibody.
Because of the public epitopes (CREGS) individuals sensitized to HLA-A2 developed an antibody which also reacted with A2, A23, A24, A68, A69, B57 and B58.
Similarly, B17, has several epitopes corresponding to public epitopes including A2, A23, A24, A68, A69. These groups of antigens which were cross reactive with a single antibody became known as the cross- reactive groups (CREGs).
Each HLA composed of functional sub unit epitope to which the antibody is attached .these epitope are of two types public epitope ( it is an epitope which can be shared by more than one HLA Ag) and private epitope ( present specifically in only one HLA Ag ).
The public epitope associated with what is called cross reactive group,(a group of antigens which react with single Ab .
This means that after transplantation and exposure to donor HLA Ag reciepient will produce the DSA and non DSA( public epitope and cross reactive group )
Mohamed Ghanem
2 years ago
Non-HLA mismatches between the donor and recipient and the alloimmune responses against these targets are a significant predictor of non-specific immune response and upgrading the immunity against the kidney allograft so causing ABMR.
As non-HLA antibodies may share public epitope with HLA antigens so causing ABM rejections despite the less HLA mismatch and negative previous cross matches before kidney transplantation.
So Non-HLA DSA may affect both short and long allograft survival.
Reinsmoen NL, Lai CH, Mirocha J, Mirocha J, Cao K, Ong G, Naim M, Wang Q, Haas M, Rafiei M, Czer L, Patel J, Kobashigawa J (2014) Increased negative impact of donor HLA-specific together with non-HLA-specific antibodies on graft outcome. Transplantation 97:595–601
Alyaa Ali
2 years ago
Malheiro J et al.,showed that NDSA are associated with an higher risk of ABMR and poorer graft survival. Importantly, NDSA adverse survival impact was restricted to non ATG-induced patients. NDSA should be taken into account when stratifying the immunological risk of a given KT.
dina omar
2 years ago
Non DSA associated with poorer short and long term graft survival and a higher decline of eGFR. KTX patients with non-donor-specific pre-transplant anti-HLA immunization at higher risk for developing de novo DSA , (ABMR).
Osama Hendam
2 years ago
Non-DSA can occur in a setting of a negative XM in asensitized patient. Non DSA antibodies it refer to antibodies to minor antigen rather than HLA ,in most of cases it is not complement fixing so the C4d stain will came negative, it cause very aggressive type of AMR and it affect the graft survival in a bad way.it almost due to share epitope or public epitope.
Nazik Mahmoud
2 years ago
Non DSA antibodies it refer to antibodies to minor antigen rather than HLA ,in most of cases it is not complement fixing so the C4d stain will came negative, it cause very aggressive type of AMR and it affect the graft survival in a bad way.it almost due to share epitope or public epitope
dalia
2 years ago
Non DSA associated with poor graft survival and development of DSA post transplant . There is increase risk of AMR in patient not receiving induction with ATg .
Wee Leng Gan
2 years ago
Non DSA developed from non donor antigens.
Kidney transplant recipients with non-donor-specific pretransplant anti-HLA immunization were at a higher risk for developing de novo DSA , antibody mediated rejections (ABMR) , had a poorer short and long term graft survival and a higher decline of the calculated GFR.
Reference :
Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transplant Immunology. Volume 63, December 2020, 101333
Jamila Elamouri
2 years ago
The recipient can have AB either against HLA-Ag or non-HLA Ag (AS anti-endothelial AB)
These Abs can be donor specific antibodies (DSA) or non-donor specific AB (NDSA) which also known as third party antibody.
DSA are against HLA-Antigens of the donor
NDSA are either against HLA-antigen or non-HLA antigens
These antibodies arise due to alloimmune or autoimmune reaction
Alloimmune exposure to antigens from external environment cause formation of the antibodies, these antibodies can attach to antigens that are not formed for them specifically as these antigens share common antibodies binding sites (epitopes). These antigens called CREGS.
Autoimmune exposure to antigens from inside the body as cell proteins.
CREGS are group of antigens that share same antibodies binding sites (public epitopes).
Any antigen has antibodies binding sites (epitopes) these epitopes are two types:
1- Public epitopes: which are shares by different antigens.
2- Private epitope: this is a specific to certain antibody as it is not present on other antigen.
presence of antibodies in the recipients whatever the type can affect the allograft survival, as compared to those without antibodies.
Mahmoud Hamada
2 years ago
Majority of Class I HLA molecules, are represented by a single parts. Among these, some share common epitopes, against which a single antibody can react against all parts presenting that specific epitope. Public epitopes are those common to all members of a cross-reactive epitope group (CREG), while private epitopes present the individual, serologically determined antigens.
Ahmed Fouad Omar
2 years ago
An epitope is an Ag AB binding site while an Eplet is the functional epitope (specific amino acid sequence)
A private epitope is specific for one HLA antigen but a public epitope is shared by many HLA antigens
CREGS: public epitope antigens of the donor cross react with a single HLA AB. So, an individual who is sensitized against one of these public epitope antigens will develop an HLA antibody which will cross react not only against this donor antigen but also against other antigens shared on this public epitope and this explains the development of apparent non donor specific HLA sensitization(NDSA) or a third party AB(i.e. sensitization against an HLA antigen which does not exist in that donor but the donor has this public epitope).Epitope matching is applied in the Euro-transplant for highly sensitized patients to avoid unacceptable antigens and avoid a positive cross match.
In 2017,Malheiro et al confirmed that NDSA are associated with poor graft outcome if strong induction with ATG is not received. Additionally, Severova et al in 2018 also confirmed that there is increased risk of AMR and graft dysfunction due to these NDSA
2) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16
3) Dr Ahmed Halawa lecture
Nandita Sugumar
2 years ago
Effect of non-DSA on short and long term graft survival
Non-HLA antibodies are typically of two types :
MHC class I chain related proteins A and B
Angiotensin II type 1 receptor
Increased risk of acute AMR leading to development of proteinuria, chronic dysfunction, graft failure form the major effects of non DSA.
Hamdy Hegazy
2 years ago
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival? Recipients with non-DSA antibodies are at increased risk of ABMR, denovo DSA production, and poor graft survival.
Abdullah Raoof
3 years ago
Patients undergoing renal transplantation frequently have non-donor-specific HLA antibodies (NDSA). There could be NDSA (e.g. a negative crossmatch in a sensitized patient), or could be donor-specific HLA antibodies (DSA) (e.g., antibody-incompatible transplantation). NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA, or due to non-specific immune upregulation.
The presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.
Some suggest that the presence of HLA antibodies, DS but also NDS, is associated with transplant failure and that their screening is an important tool for the treatment of patients who receive a kidney transplant, as they could help in discriminating between chronic rejection and nonimmune allograft dysfunction. This discrimination could have therapeutic implications and could lead to specific treatment
References
1) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
2)https://jasn.asnjournals.org/content/16/9/2804.long
3)Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005 Sep;16(9):2804-12. doi: 10.1681/ASN.2004121130.
mohamed hefzy
3 years ago
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
In post-transplant non-DSA (third party anti-HLA antibodies ) have been associated with poor renal graft outcomes.
This is due to non-specific immunological mechanisms or due to antibodies binding with shared epitopes on DSA and non-DSA. Patients with non-DSA have been shown to be associated with increased risk of AMR, increased risk of de novo DSA formation and poorer GFR and decreased death censored graft survival
AMAL Anan
3 years ago
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
Third party non DSA are HLA non DSA antibodies which is formed due to either previous transplant, blood transfusions or pregnancy.
Their roles are conteraversial ,some studies showed that they associated with lower graft survival by about 10% less than patients didn’t have HLA non DSA and biopsy proven ABMR also increased with HLA antibodies .
This is due to the link between third party anti-HLA antibodies and donor shared epitopes.
– Puplic epitopes where different antigen
(CREG )shared same epitope .
– If donor HLA antibodies shared same epitopes with antigen lead to third party anti-HLA antibodies so it will like DSA but with epitopes level .
– So matching with epitopic level leads to decrease risk and diagnosis of third part anti-HLA antibodies.
References:
1.Cardarelli F, Pascual M, Tolkoff-Rubin N, Delmonico FL, Wong W, Schoenfeld DA, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
2.Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
3.Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513
ahmed saleeh
3 years ago
*Antibodies giving rise to false positive crossmatch test.
*autoreactive; may be positive in cellular crossmatch test but not found on solid-phase assays, not clinically relevant ‘Natural’ antibodies.
Have been described in untransfused males, clinical relevance uncertain. *Antibodies generated by previous exposure to HLA specificities not present on the current donor.
May have no cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation.
May have cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
May have cross-reactivity with HLA specificities, not on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
Wael Hassan
3 years ago
3rd party or Non DSA antibodies are produced due to the phenomenon of Public epitopes and Cross Reactive Groups.
The antibody attachment site on the HLA antigen is called an epitope. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.
Non DSA antibodies are associated AMR is suspected if there is no DSA and C4d positive rejection. Non HLA antibodies could also be present in this scenario, but they are more rare than non HLA DSA or third party DSA. Non HLA DSA are also present after sensitizing events like blood transfusion, pregnancy and plasmaphresis. They are associated with high risk of ABMR .
Ahmed Omran
3 years ago
Non DSA develop due to public epitopes and phenomenon of Cross Reactive Groups. Some epitopes are shared by another antigen forming public epitopes. Cross reactive groups ;CREGs denote group of different HLA antigens that can react with a single antibody. Non HLA DSA may be cause of DSA negative ABMR with increased occurrence of ABMR if PRA >80% with NDSA if they are against Class I HLA present after sensitization like in case of blood transfusion and pregnancy .It was suggested that the presence of either DS or NDS antibodies significantly associated with lower graft survival, proteinuria and poor transplant function. Risk of development of ABMR increases with Non DSA especially if they are against Class I HLA and high levels of PRA (>80%).
nawaf yehia
3 years ago
Non DSA , which might have emerged during prior sensitization , might mount an alloresponse against the graft on the bases of shared epitopes among HLA Ag of a local population . it gives Negative XM ( unlike DSA ) . so sure it will affect graft function and survival in the short and long terms .
Batool Butt
3 years ago
Non DSA or third party anti HLA antibodies develop due to the Public epitopes and Cross Reactive Groups phenomenon. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.Non HLA DSA are a cause of DSA negative ABMR and chances of ABMR are increased if PRA >80% with NDSA if they are against Class I HLA and and also present after sensitizing events like blood transfusion, pregnancy and plasmapheresis. Several studies have suggested that the presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.The risk of development of ABMR increases with NDSA if they are against Class I HLA and with high levels of PRA (>80%). REFERENCE:
1-Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005 Sep;16(9):2804-12. doi: 10.1681/ASN.2004121130.
2-Cardarelli F, Pascual M, Tolkoff-Rubin N, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
MOHAMED Elnafadi
3 years ago
NDSA( third party DSA) could be explained by a negative cross match or negativ dsa in previously sensitized patient. antibodies may bind to shared epitope or cregs on donor specific and non donor specific HLA and increase the risk of ABMR plus graft faliure (controversial ).
in reply to dr ahmed halawa those NDSA is autoantibodies of the patient which have nega xm neg dsa formed previously in sensetized patients triggered ( pregnancy bl transfusion immunization infection previous tranx )
Alshymaa Eltahan
3 years ago
AGII Abs are associated with a significant decline in the graft GFR.
Anti endothelin Abs predict poor graft survival.
Balaji Kirushnan
3 years ago
Non DSA or third party anti HLA antibodies are a cause of DSA negative ABMR. HLA antibodies could be alloantibodies directed against polymorphic antigens or autoantibodies. The frequency of the third party Anti HLA antibodies are more in highly sensitized patients with previously failed grafts.
The 3rd party or Non DSA antibodies are produced due to the phenomenon of Public epitopes and Cross Reactive Groups.
The antibody attachment site on the HLA antigen is called an epitope. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.
Non DSA antibodies are associated AMR is suspected if there is no DSA and C4d positive rejection. Non HLA antibodies could also be present in this scenario, but they are more rare than non HLA DSA or third party DSA. Non HLA DSA are also present after sensitizing events like blood transfusion, pregnancy and plasmaphresis. They are associated with high risk of ABMR according to mahiro et al
References:
Malheiro J, Tafulo S, Dias L, Martins L, Beirão I, Castro-Henriques A. Non-Donor-Specific Anti-HLA Antibodies Have an Adverse Impact in Kidney Graft Outcomes. Am J Transplant. 2017;17 (suppl 3).
Abdul Rahim Khan
3 years ago
Kidney graft recipient may have donor specific antibodies -DSA and non donor specific antibodies-NDSA and NHLA antibodies. The NDSA are also called third party DSA. This can be exemplified by a negative cross match in very sensitized patient. These antibodies may bind with shared epitope on donor specific and non donor specific HLA and these levels can be variable with initial low levels post transplant to high level during rejection episode. DSA have detrimental effect on graft outcome however effect of non DSA is controversial .Patients who have NDSA before transplant have high risk of developing de novo DSA and ABMR, significant decrease in eGFR and poor graft outcomes. The exact mechanism is not clear and can be due to exaggerated immune response.
Michala Cioni et al . Post-transplant de novo non donor-specific HLA antibodies are not associated with poor graft outcome in non-sensitized pediatric recipients of kidney transplantation.Transpl Immunol. 2021 Apr;65:101375.
CARLOS TADEU LEONIDIO
3 years ago
Non-DAS are antibodies that affect grafts may be against antigens other than HLA antigens. The development of post-transplant antibodies against non-HLA autoantigens is associated with acute rejection and decreased long-term graft survival. They are present on endothelial cells, epithelia and monocytes.
However, these antibodies may originate from antigens that not sharing epitopes with donor mismatches, these are true Non-DSA (i.e. third-partyspecific antibodies). Its possible because epitope sensitization to nontransplant antigens pre- or posttransplantation can be the cause of the NDSA response.
Reference:
– Cai J, Terasaki PI, Mao Q, Pham T, El-Awar N, Lee JH, Rebellato L: Development of non-donorspecific HLA-DR antibodies in allograft recipients is associated with shared epitopes with mismatched donor DR antigens. Am J Transplant 2006;6:2947–2954.
Drtalib Salman
3 years ago
Non DSA Ab could be non HLA ex:(anti endothelial )or anti HLA but non DSA
its effect less than DSA but graft survival less than those no Ab
any Ab carry risk when compare with no Ab .
Murad Hemadneh
3 years ago
Anti- HLA antibodies can be classified into two groups which are:
Donor-specific Antibodies (DSA).
Non–specific Donor antibodies (NDSA) which also called “third party anti-HLA antibodies”.
Several studies have suggested that the presence of HLA antibodies correlates with poor graft survival. The presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.
NDSA levels slowly fall in the first month after transplantation, but in some patients, their levels initially rise during a rejection episode with increased synthesis of DSA. The risk of development of ABMR increases with NDSA if they are against Class I HLA and with high levels of PRA (>80%).
References:
Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
Staeck A, Khadzhynov D, Kleinsteuber A, Lehner L, Duerr M, Budde K, et al. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transplant Immunology.2020;63: 101333.
Filipe prohaska Batista
3 years ago
On short survival
Antibody pre-existing in the donor not measured by the DSA technique, such as Vimetine, Collagen or endothelial cells (MICA, MICB, AT1R). IgG1 and IgG3 predominance. Early de novo lesions with increased complement binding. Acute rejection and early graft loss.
On long survival
More related to late de novo lesions, with predominance of IgG2 and IgG4 and chronic rejection by costimulation mechanism. Complement inhibition, apoptosis of B cells, macrophages, and neutrophils can be inhibited by IVIg.
How explain the appearance of non-DSA?
Viral infections, pregnancy, vaccination, previous transplant
Public epitopes may coincide at other HLA sites, explaining sensitization and rejection in patients undergoing solid organ transplants who supposedly had specific donors. One way to predict these situations is with Epitope Matching, mainly:
1. Sensitized patients to determine which antigens are acceptable or not
2. Retransplantation for better compatibility with the previous graft
3. Plan to minimize or suspend immunosuppression
Mahmud Islam
3 years ago
NDSA (non- DSA) antibodies have a worse outcome, especially in the case of suboptimal induction. As demonstrated in 2017 by Malheiro et al the graft loss was more in patients who did not receive ATG compared to those who received ATG as induction.
Heba Wagdy
3 years ago
Effect of non-DSA on graft survival:
A study showed that pre transplant non DSA is associated with poor graft outcome compared to patients without HLA sensitization.
It increase the risk of development of de novo DSA which has negative impact on graft survival.
Epitope is the antigen antibody binding site, consists of amino acids which may be unique to single antigen or shared among several antigens “public epitope”.
so when an antibody target a public epitope, it will react against all antigens carrying that epitope so it may react in vitro with non donor specific antigen with the ability to target donor specific epitope in vivo.
The negative effect of non DSA result from binding of antibodies to shared epitopes on both donor specific HLA and non donor specific HLA and may develop due to non specific immune upregulation.
they may appear after exposure to HLA as after blood transfusion, pregnancy or previous transplant.
Staeck A, Khadzhynov D, Kleinsteuber A, Lehner L, Duerr M, Budde K, Lachmann N, Halleck F, Staeck O. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transplant immunology. 2020 Dec 1;63:101333.
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Humoral Immunity in Kidney Transplantation. 2009;162:107-16.
Shereen Yousef
3 years ago
non DSA antibodies is formed due to previous sensitization event (as during pregnancy, blood transfusion or previuos transplantions) which result in exposure to non self antigen and formation of HLA antibodies .
These antibodies are called 3rd party antibodies and there effect is still not confirmed
It may be associated with lower graft survival and the incidence of biopsy proven ABMR was increase in patients with non DSA HLA antibodies in some studies.
and other showed no clinical importance.
Some studies explained this role in rejection by the fact of shared epitopes which is antigenic and can be detected by antibodies.(1)
donor HLA might share some epitops with the antigens responsible for formation of 3rd party antibodies .(1)
Some studies showed that patients with NDS antibodies also had a significantly higher risk for transplant failure and decreased transplant function than patients without HLA antibodies . This suggested that although these patients received a transplant with good conditions of HLA matching, they remained high immunologic responders.
Non DSA Ab levels rise during a rejection episode associated with the elevation of DSA levels. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA or due to non-specific immune upregulation.(2)
References:
1- Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
2- D Briggs, D Zehnder and R M Higgins. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843.
Dalia Ali
3 years ago
NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise in
1-a rejection episode with increased synthesis of DSA.
2-antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA
3-non-specific immune upregulation.
In addition to DSA, we have observed the consistent induction of diverse, cross-reactive NDSA not only during the post-transplant course but also after graft failure, when immunosuppression is tapered prior to nephrectomy.
Reference
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
fakhriya Alalawi
3 years ago
Malheiro et al 2017 demonstrated that NDSA are associated with a higher risk of ABMR and poorer graft survival. Importantly, NDSA adverse survival impact was restricted to non ATG-induced patients. And that NDSA should be taken into account when stratifying the immunological risk of a given KT.
Similarly, Hassan S, et al, showed that Patients with ndHLAs were more likely to have rejection [p=0.004], in particular T-cell mediated [p=0.006] and graft loss [p=0.005]. This risk remained following correction for total mismatch, graft number and DGF [HR 1.85(1.20-2.86), p=0.005]. Patient loss was not significant [p=0.072]. Multivariate analysis showed that previous pregnancies [OR 2.21(1.25-3.91), p=0.006] and transfusions within the first year of transplantation [OR 1.72(1.03-2.86), p=0.039] were associated with ndHLA development.
Malheiro J, Tafulo S, Dias L, Martins L, Beirão I, Castro-Henriques A. Non-Donor-Specific Anti-HLA Antibodies Have an Adverse Impact in Kidney Graft Outcomes. Am J Transplant. 2017;17 (suppl 3).
Hassan S, Lucisano G, Santos E, McKeown D, Goodall D, Gueret-Wardle A, McLean A, Brooks P, Willicombe M, Taube D. De Novo, Non-Donor Specific HLA Antibodies Are Associated with Inferior Allograft Outcomes After Kidney and Simultaneous Kidney-Pancreas Transplantation. Am J Transplant. 2017;17 (suppl 3).
fakhriya Alalawi
3 years ago
Patients undergoing renal transplantation frequently have non-donor-specific HLA antibodies (NDSA). There could be NDSA (e.g. a negative cross-match in a sensitized patient) or could be donor-specific HLA antibodies (DSA) (e.g., antibody-incompatible transplantation). Both DSA and NDSA can be adsorbed by the graft and erratically detected in the circulation. NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA, or due to non-specific immune up-regulation. Moreover, the strong sensitization to NDSA will seriously hamper the ability to identify a compatible donor for a future transplant.
References:
· Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
· Rebellato LM, Ozawa M, Verbanac KM, Catrou P, Haisch CE, Terasaki PI. Clinical and anti-HLA antibody profile of nine renal transplant recipients with failed grafts: donor-specific and non-donor-specific antibody development. Clin Transpl. 2006:241-53. PMID: 18365382.
Innocent lule segamwenge
3 years ago
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
Non- DSA antibodies are associated with poor graft outcomes both short and long-term.
They include angiotensin Type 1 receptor antibody, ant endothelial cell antibodies,histocompatibility complex class I chain–related gene A (MICA), glomerular basement membrane protein agrin , cardiolipin , cardiac myosin , and perlecan.
These proteins are usually not polymorphic.
Using the conceptual model of Alport’s syndrome where patients born without one or two of the different forms of type IV collagen, develop antibodies against the GBM when transplanted.
Ramy Elshahat
3 years ago
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?3rd party non DSA are HLA non DSA antibodies which caused by exposure to non self HLA antibodies during pregnancy, blood transfusion or previuos transplantions
effect of 3rd party antibodies is controverse
some studies showed 3rd party antibodies associated lower graft survival around 10% less than who don’t had no 3rd party antibodies also the incidence of biopsy proven ABMR increase in patients with HLA antibodies.
and other showed no clinical importance
maybe this variation in results related to the relation of these 3rd party antibody and donor shared epitops
epitops are serial of aa which antigenic enough to be be reconized by antibodies
some different antigens(CREG) share the same epitops (public epitops) so
if the donor HLA share some epitops with the antigens responsible for formation of 3rd party antibodies so it will be like DSA but on the epitopic level
that’s why some suggest to be the matching on the epitopic level to avoid this risks and better diagnosis of possible risky 3rd party antibodies
reference
1-Cardarelli F, Pascual M, Tolkoff-Rubin N, Delmonico FL, Wong W, Schoenfeld DA, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
2.Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
3-Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513
Abdulrahman Ishag
3 years ago
Studies found that, none HLA antibodies were associated with rejection and decrease long term graft survival .
None HLA can develop under the effects of;
1-Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production.
2-The increase in HLA antibody levels during a viral infection include cross reactivity between epitopes on HLA molecules and viruses, immune up regulation secondary to a polyclonal antibody response to a single antigen, or an increase in non-self HLA expression on any non-self cells in the host expressing HLA .
Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.
Reference;
Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
Harmer AW, Haskard D, Koffman CG, Welsh KI. Novel antibodies associated with unexplained loss of renal allografts. Transpl Int. 1990;3:66–9. [PubMed] [Google Scholar]
Sherif Yusuf
3 years ago
Non DSA or third party antibodies are antibodies that develop to HLA antigens that are not donor specific.
Non DSA can develop due to sensitisation to HLA antigens either from previous blood transfusions, pregnancy or previous transplant.
The mechanism of development of non DSA :
1- Exposure of the recipient to forign HLA antigen in any sensitizing event cause the development of antibodies that can react against this antigen and also against cross reactive group (CREG) which are group of antigens that can bind the same antibody as they share the same public epitope.
For example HLA A2 share the same public epitope with HLA A 68, 69, 23, 24, B57 and B58 so if this kidney fail the patient will form antibodies against not only HLA A2 but also to all CREG.
2- Broad antigens are composed of 2 or more splits, broad antigen can bind 2 or more antibodies while split can bind only 1 antibody, exposure to split HLA antigen can lead to development of antibody to this antigen but there is high probability of forming antibody to the other splits of the broad antigen.
For example HLA A9 is a broad antigen that splits into HLA A 23, HLA A24, thus if patient is sensitized to HLA A23 there is high probability of developing antibodies against HLA A24 if exposed to the same sensitizing event.
mai shawky
3 years ago
· Many non -HLA antibodies are formed against released Ag from the graft upon exposure to traumatic events like (ischemia-reperfusion injury and surgery itself), those antibodies were corelated to both active and chronic AMR and eventually worse graft outcome.
those non-DSA are called 3dr party anti-HLA antibodies.
· The evidence of the role of non-HLA antibodies in rejection comes from rejection in HLA identically transplant couples.
· Non-HLA antibodies are either directed against:
o Polymorphicallogenic antigens in graft (different epitope matching), as we just do HLA typing..
o Autoantibodies: directed against own Ag (as endothelial Ag- anti-endothelial cell antibodies) after their exposure to traumatic event, ischemia which expose certain self antigens and break self tolerance, disturbed graft microcirculation.
the risk of their formation increase with deceased donor, any sensitizing event as re-transplantation, blood transfusion, also in case of immune system upregulation in case of infections.
sensitizing events which stimulate both de-novo DSA and non-DSA antibodies formation not essentially major events as re-transplant or blood transfusion. it can be just viral infection or even response to vaccination as COVID 19 vaccine.
Sahar elkharraz
3 years ago
Non DSA appear in sensitised patients who have exposure to pregnancy and transfusion or previous transplant
Non DSA appearance post transplant may related to patients non adherence to his drug
Manal Malik
3 years ago
Effect of non- DSA on short term predict AMR and long term predict poor graft function
Zahid Nabi
3 years ago
These are associated with poor graft outcome in both short and long term .There is increase incidence of proteinuria and ABMR .
Those who did not revieve ATG have worse prognosis
Reem Younis
3 years ago
-Non-HLA antibodies are associated with antibody-mediated rejection and C4d deposition in the absence of circulating donor-specific HLA antibodies.
-Non-HLA antibodies in transplantation can be directed against either polymorphic or nonallelic proteins.
– The development of antibodies against nonpolymorphic targets may be due to upregulation during inflammation, in response to transplantation, or when proteins are exposed to the immune system during injury. It is thought that the intragraft microenvironment or rejection may break humoral tolerance to autoantigens .
-Non-HLA DSA is associated with a greater rate of cellular rejection, lower graft function, and failed renal transplants.
– Non-HLA antibodies binding to airway epithelial cells were detected in lung transplant patients with chronic rejection, bronchiolitis obliterans syndrome (BOS), but not in patients without BOS
-Endothelial cell-binding IgM and IgG were identified using flow cytometry in about half of cardiac transplant patients with transplant coronary artery disease and patients with failed renal allografts.
-Non-HLA antibodies were found at a higher rate in cardiac and renal transplant recipients with or without rejection than in normal or wait-listed subjects, suggesting that these antigens become immunogenic during transplantation.
-Antibodies to MICA and MICB are found in renal where they associate with chronic rejection.
-In renal transplantation, antibodies recognizing glutathione-S-transferase (GST), a cytosolic enzyme that metabolizes toxins, were found in patients experiencing antibody-mediated rejection
-In some experimental studies, non-HLA antibodies do not cause injury. Referances :
-Nicole M. Valenzuela and Elaine F. Reed. Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury. Methods Mol Biol. 2013; 1034: 10.1007/978-1-62703-493-7_2.
-Zou Y, Stastny P, Susal C, Dohler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med. 2007;357:1293–1300. [PubMed] [Google Scholar]
saja Mohammed
3 years ago
Still the importance of non-HLA antibodies in kidney transplant is not completely understood, based on evidence from few studies including registry reports which shows that non-HLA antigens associated with increased risk of acute and chronic AMR and accelerated AMR in recipients of renal transplants from HLA-identical siblings.(1,2).
Non-HLA abs could be alloantibodies directed against polymorphic antigens or autoantibodies against recognize self-antigens in the endothelial cell.
the frequency of the non HLA- abs was found higher in recipients with previous history of failed graft or presensitization. Also, organs from deceased donors might have higher levels of non-HLA antibody compared to organs from LD.
AT1R antibodies were IgG1 and IgG3, associated with complement independent endovascular injury and malignant HTN ,its correlated with an increased incidence of AMR and inferior graft survival. Studies shows combination of HLA-abs with AT1R have synergistic effect and increase the risk of AMR and graft loss. Renal biopsy specimens from transplant recipients with AT1R-mediated rejection also had increased tissue factor expression and thrombotic occlusions.
Non-HLA antibodies reported to mediate renal rejection recognize autoantigens expressed by endothelial cells. Brasile et al. were the first to report a patient with pretransplant anti endothelial cell antibodies (AECA) that caused hyperacute rejection and AMR.
Non-HLA antibody directed against self-/non-HLA antigens can lead to positive cross match CDCXM, FXCM with negative DSAs detection by Luminex SAB assay , in case of no previous historic DSA s or clinical history of sensitization so likely its benign and not preclude recipients from transplant with favorable outcome unless its associated with false negative detection of true anti HLA DSAs due to low titer in previously sensitized candidate as it can increase the risk of ABMR due to the cross reactivity with the HLA DSA through immunologic memory recall Historical DSA
Negative DSA pre transplant dose not rule out the possibility of sensitization, always we should ask about historic positive testing. A careful examination of longitudinal SAB screening and prior cross matching results may reveal the presence of a historical DSA and immunologic memory against the donor antigen
There are no existing, clinically validated assays to challenge a latent memory response, determine whether low-titer DSA will remain low, or rapidly increase post transplantation following repeat exposure to the antigen. However, awareness of this potential memory recall response may affect the clinician’s decision to intensify the immunosuppressive regimen and/or post transplantation monitoring strategy.
Mainly non-donor-specific pretransplant HLA class I immunization is an independent risk factor for the development of de novo DSA, ABMR and graft loss.
One study confirm that the pretransplant circulating antibodies against AT1R higher than 30 U in kidney graft recipients consider an independent risk factor for early de novo HLA-DSA detection after transplantation(2).
References:
1-Terasaki PI. Deduction of the fraction of immunologic and non-immunologic failure in cadaver donor transplants. Clin Transpl. 2003:449–52. [PubMed: 15387129]
2. Opelz G. Collaborative Transplant S. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet. 2005; 365:1570–6. [PubMed: 15866311]
3- taeck A, Khadzhynov D, Kleinsteuber A, Lehner L, Duerr M, Budde K, Lachmann N, Halleck F, Staeck O. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transpl Immunol. 2020 Dec;63:101333.
4- Cuevas E, Arreola-Guerra JM, Hernández-Méndez EA, Salcedo I, Castelán N, Uribe-Uribe NO, Vilatobá M, Contreras-Saldívar AG, Sánchez-Cedillo AI, Ramírez JB, de Rungs D, Granados J, Morales-Buenrostro LE, Alberú J. Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies. Nephrol Dial Transplant. 2016 Oct;31(10):1738-45.
MICHAEL Farag
3 years ago
infections, immunization, blood transfusion can trigger rejection episodes and increase HLA antibodies. A recent study has shown that there is a strong association between the development of infection and increases in both breadth and strength of HLA antibodies [. The increase in the breadth of HLA antibodies was mainly due to expansion of reactivity among other antigens of a cross-reactive group (CREGs). Other studies have shown that in transplant kidney biopsies of acutely rejecting patients with viral infections the presence of plasma cell infiltrates and C4d deposition. The relationship between infection and rise in HLA antibodies is thought to be secondary to the presence of a robust memory B-cell response to the release of pro-inflammatory cytokines.
in conclusion: non DSA anti HLA antibodies have a bad impact on the graft survival
reference: Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
Thankyou for mentioning the mechanism of their generation and cross reacting CREGS. Can you answer the following questions (and this is for everybody):
1. In clinical practice how are they detected?
2.All agree they are not without bad effects specially on B cell stimulation.
3. Are you going to manage the situation.
1. In clinical practice how are they detected?
-Flowcytometric estimation of blood group antibodies.-Quantification of viral antibodies using LIAISON® analyzer.Using the LIAISON ® analyzer (DiaSorin S.p.A, Saluggia, Italy), Cytomegalovirus (CMV), Varicella Zoster (VZV) and Anti Hepatitis B Surface antigen (Anti-HBsAg) IgG antibodies were quantified from the corresponding serum samples according to manufactures instructions.
–CMV screening and prophylaxis. 2-All agree they are not without bad effects, especially on B cell stimulation. actually, I didn’t get your point prof.
3. Are you going to manage the situation.
I couldn’t get a proper answer but in my clinical practice we don’t treat it apart from prevention and treatment of infection, avoid blood transfusion as much as possible
***waiting for your comment and guide prof.
Ben Lomatayo
3 years ago
Non- DSA antibodies can leads to acute & chronic rejection and poor transplant outcomes
Pre-tranpalnt Anti-endothelial cell antibodies can cause hyper-acute rejection
Angiotesin II type1 receptor(ATR1) Ab is associated with vascular injury & malignant hypertension
LG3( Laminin-like globular domains) antibodies increases risk of chronic and vascular rejection
Collagen IV & Fibronectin autoantibodies are transplant glomerulopathy
References ;Zou Y, Stastny P, Susal C, Dohler B, Opelz G. Antibodies against MICA antigens and kidney- transplant rejection. N Engl J Med. 2007; 357:1293–300. [PubMed: 17898098] Brasile L, Rodman E, Shield CF 3rd, Clarke J, Cerilli J. The association of antivascular endothelial cell antibody with hyperacute rejection: a case report. Surgery. 1986; 99:637–40. [PubMed: 3518110] Harmer AW, Haskard D, Koffman CG, Welsh KI. Novel antibodies associated with unexplained loss of renal allografts. Transpl Int. 1990; 3:66–9. [PubMed: 2206221]
Ben please revise the following:non HLA antibodies are not directed to HLA antigens but rather to endothelial cells or anti angiotensin 2receptors.
Third party are antibodies directed to HLA which is not donor specific so they are non donor specific HLA antibodies.
Anti HlA antibodies both DSA and NDSA can adversely affect graft survival , for NDSA antibodies , they may result from sensitizing events as blood transfusion , pregnancy , infection or inflammation. They may be
1-autoreactive antibodies that give false positive results with crossmatch test but can be diagnosed by SAB
2- natural antibodies : unknown significant
Clinical significant
1- Post transplantation NDSA are associated with higher risk of ABMR and poorer graft survival, the exact mechanism is still poorly understood, it may reflect enhanced immune response status or elevated level of NDSA in contex of acute rejection episode may just be a consequence of ABMR as both DSA and NDSA were found to be elevated during rejection episodes.
Non DSA antibodies are
antibodies against non Donor antigens
Both DSA and NDSA can be adsorbed by the graft and can be detected in the circulation, in some cases remaining undetected until nephrectomy.
de novo DSA generally of greater strength than de novo NDSA
In addition to DSA, we have observed the consistent induction of diverse, cross-reactive NDSA not only during the post-transplant course but also after graft failure, when immunosuppression is tapered prior to nephrectomy.
since the strong sensitization to NDSA will seriously affected the ability to identify a compatible donor for a future transplant, this reinforce the importance of minimizing HLA mismatches between the donor and the recipient.(1)
Patients with non-donor-specific pretransplant anti-HLA immunization were at a higher risk for
1-developing de novo DSA
2-antibody mediated rejections (ABMR)
3-poorer graft survival and worse graft outcome if not received strong induction with ATG
4- higher decline of the calculated GFR.
5-In elderly patients anti-HLA immunization only had a significant influence on the development of DSA (2).
1- Rebellato LM, Ozawa M, Verbanac KM, Catrou P, Haisch CE, Terasaki PI.
Clinical Transplants 2006, Chapter 18
Clinical and Anti-HLA Antibody Profile of Nine Renal Transplant Recipients with Failed Grafts: Donor-specific and Non-donor-specific Antibody Development.
2- Anja Staeck 1, Dmytro Khadzhynov etal. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. 0.1016/j.trim.2020.101333
Thankyou Dalia for the clear explanation of their effect and the impact on further donor compatibility.
A careful initial compatible search will reduce the CREGS mechanism of their production.
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
While de novo donor-specific HLA antibodies (dndsas) have a detrimental impact on kidney graft outcome, the clinical significance of de novo non donor-specific antibodies (dnndsas) is more controversial. 20–40%of low-risk, previously non sensitized, kidney recipients will develop post-transplant de novo donor specific HLA antibodies (dndsas), leading to late AMR and graft loss in a significant proportion of patients. Somestudies have shown that the post-transplant occurrence of dnndsas in non-sensitized kidney graft recipients does not have an adverse effect on graft survival Onthe contrary, other studies have shown that kidney allografted patients who develop dnndsas were at increased risk for graft failure. Mechanisms for the induction of dnndsas have not yet been clarified.
Last edited 3 years ago by MOHAMMED GAFAR medi913911@gmail.com
Weam Elnazer
3 years ago
One research investigated the impact of pretransplant class I and II non-donor-specific anti-HLA on the immunologic outcome and graft survival in kidney transplant patients who had received a kidney transplant.
patients who had received non-donor-specific anti-HLA prior to transplantation had a greater probability of developing de novo DSA antibody-mediated rejections.
A lower death censored graft survival was seen in patients who did not get a non-donor-specific pretransplantation.
The only class I pretransplant HLA immunization, not class II pretransplant HLA immunization, was shown to be a significant independent risk factor for de novo DSA, ABMR, and mortality censored graft loss in a multivariate model.
Another research found that anti-HLA non-DSA antibodies were discovered in 50% of patients who had transplant failure, with DSA antibodies found in about 20% of patients.
Patients with anti-HLA non-DSA antibodies had a poorer graft survival rate.
-F. Cardarelli; M. Pascual; N. Tolkoff-Rubin; F. L. Delmonico; W. Wong; D. A. Schoenfeld; et al.
Dear All
How do you explain the appearance of non-DSA?
Please listen to part 2 in week 1 lecture
There is a reward for the right answer (Comprehensive Clinical Nephrology 2019)
-It may be due to upregulation during inflammation, in response to transplantation, or when proteins are exposed to the immune system during injury. It is thought that the intragraft microenvironment or rejection may break humoral tolerance to autoantigens .
Public epitope and cross-reactive groups (CREGs) which sharing many HLA antigens which can cross reactivities by single anti HLA antibody which explain non-DSA antibody appearance.
What is the difference between the public epitopes and CREGs?
Dear Dr Ahmed,
The antibody attachment site on the HLA antigen surface is called the epitope. Single HLA antigen may have different epitopes, some of which may be “private” epitopes which are unique to this specific HLA antigen. On the other hand, some epitopes are “public” epitopes that may be present on several distinct HLA antigens (1).
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody. It is the traditional (serologic) expression of the modern (molecular-based) public epitopes (1).
References:
1) Melissa Y Yeung. Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing. © 2022 UpToDate. (Accessed on 1 April 2022).
Each HLA Ag have on there surface many epitopes which are the AB attachments site these epitopes can be shared between one or more HLA Ag (public epitopes) and some are private to specific HLA Ag (private epitopes).
CREGS mean that different HLA Ags can react with single antibody.
A public epitope is antigen-antibody binding site shared by more than 1 antigen.
CREG (Cross reactive group): It is a group of antigens cross reactive with a single antibody. So all the members of CREG will have same epitope, which can be called a public epitope.
public epitope which shared by another antigens and there is private epitope which not shared by another.
The group of antigens that cross react with the single antibody called CREGs
Public epitopes ; if one antibody bind more than one similar eiptopes, they are called public epitopes. If the one antibody binds only one epitope without binding other epitopes , the eiptope is called private epitope. CREGs refers to group of antigens that have common antibody binding site.
public epitopes are an antigen-antibody binding site that can be shared by more than one antigen.
CREGs are groups of antigens that cross-react with a single antibody
epitop is the site of HLA antigens were the DSAs bound, usually represnted by certain sequence of amino acids called eplets against which the donor is mounting an antibody reaction, when thses eplets are shared between more than one HLA antigens then the same anti HLA antibody will react with different HLA antigen, some of them are non Donor soecific HLA antibodies (third party), that is why its called shared epitop.
CREGs (cross reacting groups) are set of different HLA antigens reacting with a single anti HLA antibody basically because they are sharing the same epitops.
Nearly similar things.. Pulblic epitopes found in in some HLa antigens are structural similar so one who have antibody to one epitope, He well have or develop antibodies to the other HLA antigen. fore example: patients sensitized to HLA A2 probably well develop antigens to : A23, A24, A68, A69, B57 &B58
Antibodies that can be detected in transplantation and may impact graft survival are classified into :
Antibodies can be :
HLA DSA ( HLA antibodies in recipient against donor )
or
HLA non DSA also named third party anti-HLA antibodies (HLA antibodies not against the donor )
Or
Non HLA as Anti-endothelial cell antibodies , Angiotesin II type1 receptor(ATR1)
Explanation of NDSA
exposure to sensitizing event as pregnancy , blood transfusion or infection.
may be due to
1- non specific response due to formation of polyclonal Ab in response to single Ag
2- Ab formation against shared epitopes between DSA and NDSA HLA molecules or against CREG
3- Cross reactivity of common epitopes or antigenically related HLA molecules and an infectious agent that may also trigger robust activation of memory cells .
4- increase expression of non self self HLA Ag on the recipient cells as the level of NDSA commonly increase during rejection episodes in association with rising DSA levels .
this leads to poor graft outcomes and increased risk of AMR
Public epitopes it is HLA binding site called epitopes with functional amino acid called epilets when group of epitopes have similarity to share with different HLA antigens and react with single Ab called puplic .
GREGs groups of antigens react with single Ab.
The public epitope is shared by more than one antigen while CREGs is a group of antigens which react with same antibody . So all antigens in CREGs will have same epitope and it will called public epitope
Difference between public epitopes and CREGs :
Public epitopes refer to epitopes that are shared by more than one HLA antigen. HLA antibodies will show reactivity with the antigen that contains the public epitope.
Cross reactive groups (CREGs) are a group of antigens that share a public epitope. This is seen by a specific antibody that reacts with all of them.
Antibodies bind to HLA antigens on target epitopes,Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross-reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes.
How do you explain the appearance of non-DSA
The appearance of non-DSA is due to sensitization event like DSA. because non-DSA for one recipient could be donor specific for another. So sensitization events like blood transfusion, pregnancies and re-transplant are common. Another trigger for non-DSA is immune response to vaccinations or viral illnesses like COVID19.
I think this is because of public epitopes
The renal transplant patients frequently have non-donor-specific HLA antibodies (NDSA),a negative crossmatch in a sensitized patient. Usually NDSA levels slowly fall in the first month after transplantation, but in another cases some patients the level of NDSA rise during the time of rejection with increase in the level of DSA. The appearance of NDSA could be due antibodies against shared(public) epitopes or due to immune upregulation secondary to bacterial, viral infections or some types of vaccinations (Generation of memory cells either T or B memory cells which just need very low activation stimulus (antigen stimulation) to activate their responses and unfraternally they are very resistant to conventional immunosuppression.
How do you explain the appearance of non-DSA?
——————————————————————-
Non-DSA can occur in a setting of a negative XM in a sensitized patient.
Levels slowly fall in the 1st post-transplant month, & may initially rise during AR with increased synthesis of DSA.
This is explained by antibodies binding with shared epitopes on DSA & Non-DSA; giving rise to apparently non-donor specific HLA sensitization, although the epitopes are indeed donor specific.
Alternatively it could be due to non-specific immune up-regulation.
====================================================================
References:
1. Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
2. Applied Transplant Immunology; Case-based Discussion(Part 1),Lecture by Ahmed Halawa
after renal transplantation, there are antibodies formed in the recipient which may be non DSA (with negative cross match), or DSA (positive cross match), these non DSA can fall in the 1st month post transplant , or may increase and persist predispose to rejection through immunological upregulation response or increase DSA , shared epitopes between DSA and non DSA
so it may be a new way to know or predict rejection episodes in such patients
D Briggs, D Zehnder, R M Higgins. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications.
Contrib Nephrol. 2009;162:107-16.
Dear Dr Ahmed,
How do you explain the appearance of non-DSA?
I think that public epitopes of the donor HLA antigens are responsible for the development of non-DSA in solid organ transplant recipients.
References:
1) Melissa Y Yeung. Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing. © 2022 UpToDate. (Accessed on 1 April 2022).
How do you explain the appearance of non-DSA?
non-donor specific antibodies refere to recipients specific allo -or autoantibodies with negative crossmatch and negative DSA in previously sensitized recipients ususally non-DSA fall immediatly in the first month post transplant but in some cases their expression increaseed or triggered during, acute ischemic injury (IRI) ,infections ( viral ),immunazation,blood group incompatiblity due to epitope sharing and crossreactivity with donor specific antigens or nondonor HLA antigens .
References:
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
4% of acute rejection episodes among transplant recipients are caused by NDSA. Presence of NDSA can predict poor graft survival especially in recipients didn’t receive induction or receive anti-IL-2 R, but patients who use induction with T cell depleting agent had better prognosis.
HLA loci had a wide polymorphic regions (>25,000 HLA alleles) . The different alleles can share epitopes with each others . Shared epitopes can cause alloimmunity by B cells epitopes(BE). HLA that shared BE called CREG, & antibodies against donor CREG (NDSA) associated with increased risk of early ABMR.
The development of post-transplant antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, recent studies provide compelling experimental and clinical findings demonstrating that antibodies directed against autoantigens contribute to the process of antibody-mediated acute and chronic rejection. Important areas for investigation remain understanding the mechanisms underlying the production of autoantibodies in the setting of organ transplantation. Ischaemia- reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ- derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production. Th17 cells are essential in the orchestrating autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promoteallograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non- HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.
immunity to non- HLA antigens also portends poorer long-term allograft outcome.
Non-HLA antibodies are classified into two main categories: alloantibodies directed against polymorphic antigens that differ between the recipient and donor, and antibodies that recognize self-antigens — autoantibodies. As the vasculature is at the interface of the recipient immune system and the transplanted organ, a substantial proportion of the non- HLA antibodies reported to mediate renal rejection recognize autoantigens expressed by endothelial cells.
despite generating autoantibodies following transplantation, the majority of patients did not experience rejection or graft dysfunction. This finding suggests that the pathogenicity of the autoantibodies is conditional upon other factors such as ligand expression, ischaemic injury and/or the state of inflammation within the microenvironment of the allograft. The expression of autoantigens on the endothelium can vary widely depending upon their anatomical location, vessel type and inflammatory milieu, which might pose challenges to ascribe clinical relevance to non-HLA autoantibodies.
NDSA Traditionally dismissed as a risk factor
Malheiro et al 2017 demonstrated that NDSA are associated with worse graft outcome if not received strong induction with ATG
Severova et al 2018 also confirmed the increased risk of AMR and graft dysfunction due to NDSA
Crossreactivity between public epitobs has a major role in the development of NDSA ,this decrease after one month post-transplantation but upregulated after any trigger like infection,immunization or blood transfusion.
Reference:
The importance of non-HLA antibodies in transplantation
Qiuheng Zhang and Elaine F. Reed
UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
Dr Ahmed Halawa lecture.
Non-donor-specific HLA antibodies may be –
1) Antibodies giving rise to false positive crossmatch – like autoantibodies.
2) Natural antibodies: in untransfused males, against cross-reactive epitopes found in microorganisms, ingested proteins and allergens.
3) Antibodies formed due to exposure to HLA not present in the current donor: levels may rise on immune upregulation or due to antigen-specific stimulation (if have cross-reactivity with the HLA on the donor – public epitope).
4) Antibodies formed by exposure to HLA present on the current donor having cross-reactivity with HLA specificities not on the current donor.
References:
1) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
2) Morales-Buenrostro LE, Terasaki PI, Marino-Vázquez LA, Lee JH, El-Awar N, Alberú J. “Natural” human leukocyte antigen antibodies found in nonalloimmunized healthy males. Transplantation. 2008 Oct 27;86(8):1111-5. doi: 10.1097/TP.0b013e318186d87b. PMID: 18946350.
after exposure to HLA antigens during pregnancy ,blood tx ,previous tx and previous immunization or infection >>> antibodies formed against public epitops and CREG
It could be due to antibodies binding to shared epitopes on non-donor-specific HLA, or due to non-specific immune upregulation.
reference
Remuzzi G, Chiaramonte S, Perico N, Ronco C (eds) (eds): Humoral Immunity in Kidney Transplantation. Contrib Nephrol. Basel, Karger, 2009, vol 162, pp 107-116
When it comes to the formation of NDSA, crossreactivity across public epitopes plays a significant role. This decreases after one-month post-transplantation but is increased following any trigger such as infection, vaccination, or blood transfusion.
Non DSA development in un-sensitized patients is associated with pregnancy and transfusions.
Reference:
Briggs D, Zehnder D, Higgins RM. Development of Non-Donor-Specific HLA Antibodies after Kidney Transplantation: Frequency and Clinical Implications. Contrib Nephrol. Basel, Karger, 2009, vol 162, pp 107–116.
Epitops are sites of HLA antigen recognized by the Anti HLA antibodies , this recognition depends on a certain amino acids sequence called eplets(which are the functional epitops) , each HLA molecule has many epitops. In some cases those eplets are shared between different HLA antigens and its called public epitops, leading to the cross reaction of same anti HLA antibody with different HLA antigens and some times it might cause a reaction with non Donor HLA antigen (non existing) called non Donor specific antibody non _DSAs, third party HLA Antibodies. Its lmportant and associated with poor allograft outcome in patients who did not receive ATG induction in the anti rejection protocol at time of transplantation.
Reference.:prof.Ahmad Halawa Lecture.
Viral infections, pregnancy, vaccination, previous transplant
Public epitopes may coincide at other HLA sites, explaining sensitization and rejection in patients undergoing solid organ transplants who supposedly had specific donors. One way to predict these situations is with Epitope Matching, mainly:
1. Sensitized patients to determine which antigens are acceptable or not
2. Retransplantation for better compatibility with the previous graft
3. Plan to minimize or suspend immunosuppression
NDSA may result from exposure to sensitizing event as pregnancy , blood transfusion or infection. The proposed underlying pathogenesis may be
1- Immune up regulation with non specific response secondary to formation of polyclonal Ab in response to single Ag
2- Ab formation against shared epitopes between DSA and NDSA HLA molecules or against CREG
3- Cross reactivity of common epitopes or antigenically related HLA molecules and an infectious agent that may also trigger robust activation of memory cells .
4- increase expression of non self self HLA Ag on the recipient cells as the level of NDSA commonly increase during rejection episodes in association with rising DSA levels .
Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
NDSA
-level slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA.
-This could be due to antibodies binding with shared epitopes on donor-specific and nondonor-specific HLA, or due to non-specific immune upregulation.
Antibodies giving rise to false positive crossmatch test
• May be autoreactive; may be positive in cellular crossmatch test but not found on solid phase assays, not clinically relevant
‘Natural’ antibodies
• Have been described in untransfused males, clinical relevance uncertain
Antibodies generated by previous exposure to HLA specificities not present on current donor
• May have no cross-reactivity with HLA specificities on current donor, levels may rise due to immune upregulation
• May have cross-reactivity with HLA specificities on current donor, levels may rise due to immune upregulation or to antigen-specific stimulation
Antibodies generated by exposure to HLA specificities present on current donor
• May have cross-reactivity with HLA specificities not on the current donor, levels may rise due to immune upregulation or to antigen-specific stimulation
Non-DSA (third party DSA) were traditionally dismissed as a risk factor for allograft failure, Malheiro et al (2017) demonstrated that Non-DSA were associated with worse graft outcome if not received strong induction with ATG>> their appearance mostly explained due to the presence of shared epitopes within the HLA Ags
Actually, HLA Abs are directed against private specifications such as HLA-A1 which recognize an epitope that is unique to a particular HLA or a limited family of closely related alleles., Abs directed public specifications (public epitopes) like Bw6, which are shared by more than one HLA molecule are responsible for cross reactivity observed in HLA allo-antiserum the so called CREG.
It can be due to immune upregulation or due to antibodies binding with shared epitope on DSA and NDS HLA
The appearance of non-DSA’s may be due to exposure to HLA not present in the current donor , or autoantibodies or natural antibodies .
Public Epitope and Cross-Reactive Groups (CREGS)
Shared by many HLA antigens and can cause cross reactivities by a single anti HLA antibody.
Because of the public epitopes (CREGS) individuals sensitized to HLA-A2 developed an antibody which also reacted with A2, A23, A24, A68, A69, B57 and B58.
Similarly, B17, has several epitopes corresponding to public epitopes including A2, A23, A24, A68, A69. These groups of antigens which were cross reactive with a single antibody became known as the cross- reactive groups (CREGs).
Each HLA composed of functional sub unit epitope to which the antibody is attached .these epitope are of two types public epitope ( it is an epitope which can be shared by more than one HLA Ag) and private epitope ( present specifically in only one HLA Ag ).
The public epitope associated with what is called cross reactive group,(a group of antigens which react with single Ab .
This means that after transplantation and exposure to donor HLA Ag reciepient will produce the DSA and non DSA( public epitope and cross reactive group )
Non-HLA mismatches between the donor and recipient and the alloimmune responses against these targets are a significant predictor of non-specific immune response and upgrading the immunity against the kidney allograft so causing ABMR.
As non-HLA antibodies may share public epitope with HLA antigens so causing ABM rejections despite the less HLA mismatch and negative previous cross matches before kidney transplantation.
So Non-HLA DSA may affect both short and long allograft survival.
Reinsmoen NL, Lai CH, Mirocha J, Mirocha J, Cao K, Ong G, Naim M, Wang Q, Haas M, Rafiei M, Czer L, Patel J, Kobashigawa J (2014) Increased negative impact of donor HLA-specific together with non-HLA-specific antibodies on graft outcome. Transplantation 97:595–601
Malheiro J et al.,showed that NDSA are associated with an higher risk of ABMR and poorer graft survival. Importantly, NDSA adverse survival impact was restricted to non ATG-induced patients. NDSA should be taken into account when stratifying the immunological risk of a given KT.
Non DSA associated with poorer short and long term graft survival and a higher decline of eGFR. KTX patients with non-donor-specific pre-transplant anti-HLA immunization at higher risk for developing de novo DSA , (ABMR).
Non-DSA can occur in a setting of a negative XM in a sensitized patient.
Non DSA antibodies it refer to antibodies to minor antigen rather than HLA ,in most of cases it is not complement fixing so the C4d stain will came negative, it cause very aggressive type of AMR and it affect the graft survival in a bad way.it almost due to share epitope or public epitope.
Non DSA antibodies it refer to antibodies to minor antigen rather than HLA ,in most of cases it is not complement fixing so the C4d stain will came negative, it cause very aggressive type of AMR and it affect the graft survival in a bad way.it almost due to share epitope or public epitope
Non DSA associated with poor graft survival and development of DSA post transplant . There is increase risk of AMR in patient not receiving induction with ATg .
Non DSA developed from non donor antigens.
Kidney transplant recipients with non-donor-specific pretransplant anti-HLA immunization were at a higher risk for developing de novo DSA , antibody mediated rejections (ABMR) , had a poorer short and long term graft survival and a higher decline of the calculated GFR.
Reference :
Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transplant Immunology. Volume 63, December 2020, 101333
The recipient can have AB either against HLA-Ag or non-HLA Ag (AS anti-endothelial AB)
These Abs can be donor specific antibodies (DSA) or non-donor specific AB (NDSA) which also known as third party antibody.
DSA are against HLA-Antigens of the donor
NDSA are either against HLA-antigen or non-HLA antigens
These antibodies arise due to alloimmune or autoimmune reaction
Alloimmune exposure to antigens from external environment cause formation of the antibodies, these antibodies can attach to antigens that are not formed for them specifically as these antigens share common antibodies binding sites (epitopes). These antigens called CREGS.
Autoimmune exposure to antigens from inside the body as cell proteins.
CREGS are group of antigens that share same antibodies binding sites (public epitopes).
Any antigen has antibodies binding sites (epitopes) these epitopes are two types:
1- Public epitopes: which are shares by different antigens.
2- Private epitope: this is a specific to certain antibody as it is not present on other antigen.
presence of antibodies in the recipients whatever the type can affect the allograft survival, as compared to those without antibodies.
Majority of Class I HLA molecules, are represented by a single parts. Among these, some share common epitopes, against which a single antibody can react against all parts presenting that specific epitope. Public epitopes are those common to all members of a cross-reactive epitope group (CREG), while private epitopes present the individual, serologically determined antigens.
An epitope is an Ag AB binding site while an Eplet is the functional epitope (specific amino acid sequence)
A private epitope is specific for one HLA antigen but a public epitope is shared by many HLA antigens
CREGS: public epitope antigens of the donor cross react with a single HLA AB. So, an individual who is sensitized against one of these public epitope antigens will develop an HLA antibody which will cross react not only against this donor antigen but also against other antigens shared on this public epitope and this explains the development of apparent non donor specific HLA sensitization(NDSA) or a third party AB(i.e. sensitization against an HLA antigen which does not exist in that donor but the donor has this public epitope).Epitope matching is applied in the Euro-transplant for highly sensitized patients to avoid unacceptable antigens and avoid a positive cross match.
In 2017,Malheiro et al confirmed that NDSA are associated with poor graft outcome if strong induction with ATG is not received. Additionally, Severova et al in 2018 also confirmed that there is increased risk of AMR and graft dysfunction due to these NDSA
References:
1) Melissa Y Yeung. Kidney transplantation in adults: Overview of HLA sensitization and cross match testing. © 2022 Up To Date. (Accessed on 1 April 2022).
2) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16
3) Dr Ahmed Halawa lecture
Effect of non-DSA on short and long term graft survival
Non-HLA antibodies are typically of two types :
Increased risk of acute AMR leading to development of proteinuria, chronic dysfunction, graft failure form the major effects of non DSA.
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
Recipients with non-DSA antibodies are at increased risk of ABMR, denovo DSA production, and poor graft survival.
Patients undergoing renal transplantation frequently have non-donor-specific HLA antibodies (NDSA). There could be NDSA (e.g. a negative crossmatch in a sensitized patient), or could be donor-specific HLA antibodies (DSA) (e.g., antibody-incompatible transplantation). NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA, or due to non-specific immune upregulation.
The presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.
Some suggest that the presence of HLA antibodies, DS but also NDS, is associated with transplant failure and that their screening is an important tool for the treatment of patients who receive a kidney transplant, as they could help in discriminating between chronic rejection and nonimmune allograft dysfunction. This discrimination could have therapeutic implications and could lead to specific treatment
References
1) Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
2)https://jasn.asnjournals.org/content/16/9/2804.long
3)Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005 Sep;16(9):2804-12. doi: 10.1681/ASN.2004121130.
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
In post-transplant non-DSA (third party anti-HLA antibodies ) have been associated with poor renal graft outcomes.
This is due to non-specific immunological mechanisms or due to antibodies binding with shared epitopes on DSA and non-DSA. Patients with non-DSA have been shown to be associated with increased risk of AMR, increased risk of de novo DSA formation and poorer GFR and decreased death censored graft survival
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
Third party non DSA are HLA non DSA antibodies which is formed due to either previous transplant, blood transfusions or pregnancy.
Their roles are conteraversial ,some studies showed that they associated with lower graft survival by about 10% less than patients didn’t have HLA non DSA and biopsy proven ABMR also increased with HLA antibodies .
This is due to the link between third party anti-HLA antibodies and donor shared epitopes.
– Puplic epitopes where different antigen
(CREG )shared same epitope .
– If donor HLA antibodies shared same epitopes with antigen lead to third party anti-HLA antibodies so it will like DSA but with epitopes level .
– So matching with epitopic level leads to decrease risk and diagnosis of third part anti-HLA antibodies.
References:
1.Cardarelli F, Pascual M, Tolkoff-Rubin N, Delmonico FL, Wong W, Schoenfeld DA, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
2.Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
3.Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513
*Antibodies giving rise to false positive crossmatch test.
*autoreactive; may be positive in cellular crossmatch test but not found on solid-phase assays, not clinically relevant ‘Natural’ antibodies.
Have been described in untransfused males, clinical relevance uncertain. *Antibodies generated by previous exposure to HLA specificities not present on the current donor.
May have no cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation.
May have cross-reactivity with HLA specificities on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
May have cross-reactivity with HLA specificities, not on the current donor, levels may rise due to immune upregulation or antigen-specific stimulation.
3rd party or Non DSA antibodies are produced due to the phenomenon of Public epitopes and Cross Reactive Groups.
The antibody attachment site on the HLA antigen is called an epitope. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.
Non DSA antibodies are associated AMR is suspected if there is no DSA and C4d positive rejection. Non HLA antibodies could also be present in this scenario, but they are more rare than non HLA DSA or third party DSA. Non HLA DSA are also present after sensitizing events like blood transfusion, pregnancy and plasmaphresis. They are associated with high risk of ABMR .
Non DSA develop due to public epitopes and phenomenon of Cross Reactive Groups. Some epitopes are shared by another antigen forming public epitopes. Cross reactive groups ;CREGs denote group of different HLA antigens that can react with a single antibody. Non HLA DSA may be cause of DSA negative ABMR with increased occurrence of ABMR if PRA >80% with NDSA if they are against Class I HLA present after sensitization like in case of blood transfusion and pregnancy .It was suggested that the presence of either DS or NDS antibodies significantly associated with lower graft survival, proteinuria and poor transplant function. Risk of development of ABMR increases with Non DSA especially if they are against Class I HLA and high levels of PRA (>80%).
Non DSA , which might have emerged during prior sensitization , might mount an alloresponse against the graft on the bases of shared epitopes among HLA Ag of a local population . it gives Negative XM ( unlike DSA ) . so sure it will affect graft function and survival in the short and long terms .
Non DSA or third party anti HLA antibodies develop due to the Public epitopes and Cross Reactive Groups phenomenon. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.Non HLA DSA are a cause of DSA negative ABMR and chances of ABMR are increased if PRA >80% with NDSA if they are against Class I HLA and and also present after sensitizing events like blood transfusion, pregnancy and plasmapheresis. Several studies have suggested that the presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.The risk of development of ABMR increases with NDSA if they are against Class I HLA and with high levels of PRA (>80%).
REFERENCE:
1-Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005 Sep;16(9):2804-12. doi: 10.1681/ASN.2004121130.
2-Cardarelli F, Pascual M, Tolkoff-Rubin N, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
NDSA( third party DSA) could be explained by a negative cross match or negativ dsa in previously sensitized patient. antibodies may bind to shared epitope or cregs on donor specific and non donor specific HLA and increase the risk of ABMR plus graft faliure (controversial ).
in reply to dr ahmed halawa those NDSA is autoantibodies of the patient which have nega xm neg dsa formed previously in sensetized patients triggered ( pregnancy bl transfusion immunization infection previous tranx )
Non DSA or third party anti HLA antibodies are a cause of DSA negative ABMR. HLA antibodies could be alloantibodies directed against polymorphic antigens or autoantibodies. The frequency of the third party Anti HLA antibodies are more in highly sensitized patients with previously failed grafts.
The 3rd party or Non DSA antibodies are produced due to the phenomenon of Public epitopes and Cross Reactive Groups.
The antibody attachment site on the HLA antigen is called an epitope. Single HLA antigen will have epitopes which are unique to the HLA and not shared by other HLA antigen(private epitope). Some epitopes are shared by another antigen which are called public epitopes.
Cross reactive groups (CREGs) describe a group of different HLA antigens that can react with a single antibody.
Non DSA antibodies are associated AMR is suspected if there is no DSA and C4d positive rejection. Non HLA antibodies could also be present in this scenario, but they are more rare than non HLA DSA or third party DSA. Non HLA DSA are also present after sensitizing events like blood transfusion, pregnancy and plasmaphresis. They are associated with high risk of ABMR according to mahiro et al
References:
Kidney graft recipient may have donor specific antibodies -DSA and non donor specific antibodies-NDSA and NHLA antibodies. The NDSA are also called third party DSA. This can be exemplified by a negative cross match in very sensitized patient. These antibodies may bind with shared epitope on donor specific and non donor specific HLA and these levels can be variable with initial low levels post transplant to high level during rejection episode. DSA have detrimental effect on graft outcome however effect of non DSA is controversial .Patients who have NDSA before transplant have high risk of developing de novo DSA and ABMR, significant decrease in eGFR and poor graft outcomes. The exact mechanism is not clear and can be due to exaggerated immune response.
Michala Cioni et al . Post-transplant de novo non donor-specific HLA antibodies are not associated with poor graft outcome in non-sensitized pediatric recipients of kidney transplantation.Transpl Immunol. 2021 Apr;65:101375.
Non-DAS are antibodies that affect grafts may be against antigens other than HLA antigens. The development of post-transplant antibodies against non-HLA autoantigens is associated with acute rejection and decreased long-term graft survival. They are present on endothelial cells, epithelia and monocytes.
However, these antibodies may originate from antigens that not sharing epitopes with donor mismatches, these are true Non-DSA (i.e. third-partyspecific antibodies). Its possible because epitope sensitization to nontransplant antigens pre- or posttransplantation can be the cause of the NDSA response.
Reference:
– Cai J, Terasaki PI, Mao Q, Pham T, El-Awar N, Lee JH, Rebellato L: Development of non-donorspecific HLA-DR antibodies in allograft recipients is associated with shared epitopes with mismatched donor DR antigens. Am J Transplant 2006;6:2947–2954.
Non DSA Ab could be non HLA ex:(anti endothelial )or anti HLA but non DSA
its effect less than DSA but graft survival less than those no Ab
any Ab carry risk when compare with no Ab .
Anti- HLA antibodies can be classified into two groups which are:
Several studies have suggested that the presence of HLA antibodies correlates with poor graft survival. The presence of either DS or NDS antibodies significantly correlated with lower graft survival, poor transplant function, and proteinuria.
NDSA levels slowly fall in the first month after transplantation, but in some patients, their levels initially rise during a rejection episode with increased synthesis of DSA. The risk of development of ABMR increases with NDSA if they are against Class I HLA and with high levels of PRA (>80%).
References:
On short survival
Antibody pre-existing in the donor not measured by the DSA technique, such as Vimetine, Collagen or endothelial cells (MICA, MICB, AT1R). IgG1 and IgG3 predominance. Early de novo lesions with increased complement binding. Acute rejection and early graft loss.
On long survival
More related to late de novo lesions, with predominance of IgG2 and IgG4 and chronic rejection by costimulation mechanism. Complement inhibition, apoptosis of B cells, macrophages, and neutrophils can be inhibited by IVIg.
How explain the appearance of non-DSA?
Viral infections, pregnancy, vaccination, previous transplant
Public epitopes may coincide at other HLA sites, explaining sensitization and rejection in patients undergoing solid organ transplants who supposedly had specific donors. One way to predict these situations is with Epitope Matching, mainly:
1. Sensitized patients to determine which antigens are acceptable or not
2. Retransplantation for better compatibility with the previous graft
3. Plan to minimize or suspend immunosuppression
NDSA (non- DSA) antibodies have a worse outcome, especially in the case of suboptimal induction. As demonstrated in 2017 by Malheiro et al the graft loss was more in patients who did not receive ATG compared to those who received ATG as induction.
Effect of non-DSA on graft survival:
A study showed that pre transplant non DSA is associated with poor graft outcome compared to patients without HLA sensitization.
It increase the risk of development of de novo DSA which has negative impact on graft survival.
Epitope is the antigen antibody binding site, consists of amino acids which may be unique to single antigen or shared among several antigens “public epitope”.
so when an antibody target a public epitope, it will react against all antigens carrying that epitope so it may react in vitro with non donor specific antigen with the ability to target donor specific epitope in vivo.
The negative effect of non DSA result from binding of antibodies to shared epitopes on both donor specific HLA and non donor specific HLA and may develop due to non specific immune upregulation.
they may appear after exposure to HLA as after blood transfusion, pregnancy or previous transplant.
Staeck A, Khadzhynov D, Kleinsteuber A, Lehner L, Duerr M, Budde K, Lachmann N, Halleck F, Staeck O. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transplant immunology. 2020 Dec 1;63:101333.
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Humoral Immunity in Kidney Transplantation. 2009;162:107-16.
non DSA antibodies is formed due to previous sensitization event (as during pregnancy, blood transfusion or previuos transplantions) which result in exposure to non self antigen and formation of HLA antibodies .
These antibodies are called 3rd party antibodies and there effect is still not confirmed
It may be associated with lower graft survival and the incidence of biopsy proven ABMR was increase in patients with non DSA HLA antibodies in some studies.
and other showed no clinical importance.
Some studies explained this role in rejection by the fact of shared epitopes which is antigenic and can be detected by antibodies.(1)
donor HLA might share some epitops with the antigens responsible for formation of 3rd party antibodies .(1)
Some studies showed that patients with NDS antibodies also had a significantly higher risk for transplant failure and decreased transplant function than patients without HLA antibodies . This suggested that although these patients received a transplant with good conditions of HLA matching, they remained high immunologic responders.
Non DSA Ab levels rise during a rejection episode associated with the elevation of DSA levels. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA or due to non-specific immune upregulation.(2)
References:
1- Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
2- D Briggs, D Zehnder and R M Higgins. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843.
NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise in
1-a rejection episode with increased synthesis of DSA.
2-antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA
3-non-specific immune upregulation.
In addition to DSA, we have observed the consistent induction of diverse, cross-reactive NDSA not only during the post-transplant course but also after graft failure, when immunosuppression is tapered prior to nephrectomy.
Reference
Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
Malheiro et al 2017 demonstrated that NDSA are associated with a higher risk of ABMR and poorer graft survival. Importantly, NDSA adverse survival impact was restricted to non ATG-induced patients. And that NDSA should be taken into account when stratifying the immunological risk of a given KT.
Similarly, Hassan S, et al, showed that Patients with ndHLAs were more likely to have rejection [p=0.004], in particular T-cell mediated [p=0.006] and graft loss [p=0.005]. This risk remained following correction for total mismatch, graft number and DGF [HR 1.85(1.20-2.86), p=0.005]. Patient loss was not significant [p=0.072]. Multivariate analysis showed that previous pregnancies [OR 2.21(1.25-3.91), p=0.006] and transfusions within the first year of transplantation [OR 1.72(1.03-2.86), p=0.039] were associated with ndHLA development.
Patients undergoing renal transplantation frequently have non-donor-specific HLA antibodies (NDSA). There could be NDSA (e.g. a negative cross-match in a sensitized patient) or could be donor-specific HLA antibodies (DSA) (e.g., antibody-incompatible transplantation). Both DSA and NDSA can be adsorbed by the graft and erratically detected in the circulation. NDSA levels slowly fall in the first month after transplantation, but in some patients their levels initially rise during a rejection episode with increased synthesis of DSA. This could be due to antibodies binding with shared epitopes on donor-specific and non-donor-specific HLA, or due to non-specific immune up-regulation. Moreover, the strong sensitization to NDSA will seriously hamper the ability to identify a compatible donor for a future transplant.
References:
· Briggs D, Zehnder D, Higgins RM. Development of non-donor-specific HLA antibodies after kidney transplantation: frequency and clinical implications. Contrib Nephrol. 2009;162:107-16. doi: 10.1159/000170843. Epub 2008 Oct 31. PMID: 19001818.
· Rebellato LM, Ozawa M, Verbanac KM, Catrou P, Haisch CE, Terasaki PI. Clinical and anti-HLA antibody profile of nine renal transplant recipients with failed grafts: donor-specific and non-donor-specific antibody development. Clin Transpl. 2006:241-53. PMID: 18365382.
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?
Non- DSA antibodies are associated with poor graft outcomes both short and long-term.
They include angiotensin Type 1 receptor antibody, ant endothelial cell antibodies, histocompatibility complex class I chain–related gene A (MICA), glomerular basement membrane protein agrin , cardiolipin , cardiac myosin , and perlecan.
These proteins are usually not polymorphic.
Using the conceptual model of Alport’s syndrome where patients born without one or two of the different forms of type IV collagen, develop antibodies against the GBM when transplanted.
What is effect of non-DSA (third party anti-HLA antibodies) on short and the long-term graft survival?3rd party non DSA are HLA non DSA antibodies which caused by exposure to non self HLA antibodies during pregnancy, blood transfusion or previuos transplantions
effect of 3rd party antibodies is controverse
some studies showed 3rd party antibodies associated lower graft survival around 10% less than who don’t had no 3rd party antibodies also the incidence of biopsy proven ABMR increase in patients with HLA antibodies.
and other showed no clinical importance
maybe this variation in results related to the relation of these 3rd party antibody and donor shared epitops
epitops are serial of aa which antigenic enough to be be reconized by antibodies
some different antigens(CREG) share the same epitops (public epitops) so
if the donor HLA share some epitops with the antigens responsible for formation of 3rd party antibodies so it will be like DSA but on the epitopic level
that’s why some suggest to be the matching on the epitopic level to avoid this risks and better diagnosis of possible risky 3rd party antibodies
reference
1-Cardarelli F, Pascual M, Tolkoff-Rubin N, Delmonico FL, Wong W, Schoenfeld DA, et al. Prevalence and significance of anti-HLA and donor-specific antibodies long-term after renal transplantation. Transpl Int. 2005;18:532–540.
2.Hourmant M, Cesbron-Gautier A, Terasaki PI, Mizutani K, Moreau A, Meurette A, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol. 2005;16:2804–2812
3-Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87:1505–1513
Studies found that, none HLA antibodies were associated with rejection and decrease long term graft survival .
None HLA can develop under the effects of;
1-Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens in the form of soluble antigens, extracellular vesicles or apoptotic bodies that are presented in context of the transplant recipient’s antigen presenting cells to stimulate autoantibody production.
2-The increase in HLA antibody levels during a viral infection include cross reactivity between epitopes on HLA molecules and viruses, immune up regulation secondary to a polyclonal antibody response to a single antigen, or an increase in non-self HLA expression on any non-self cells in the host expressing HLA .
Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection and the development of targeted therapies to treat these rejections are sorely needed to improve both transplant and patient survival.
Reference;
Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
Harmer AW, Haskard D, Koffman CG, Welsh KI. Novel antibodies associated with unexplained loss of renal allografts. Transpl Int. 1990;3:66–9. [PubMed] [Google Scholar]
Non DSA or third party antibodies are antibodies that develop to HLA antigens that are not donor specific.
Non DSA can develop due to sensitisation to HLA antigens either from previous blood transfusions, pregnancy or previous transplant.
The mechanism of development of non DSA :
1- Exposure of the recipient to forign HLA antigen in any sensitizing event cause the development of antibodies that can react against this antigen and also against cross reactive group (CREG) which are group of antigens that can bind the same antibody as they share the same public epitope.
For example HLA A2 share the same public epitope with HLA A 68, 69, 23, 24, B57 and B58 so if this kidney fail the patient will form antibodies against not only HLA A2 but also to all CREG.
2- Broad antigens are composed of 2 or more splits, broad antigen can bind 2 or more antibodies while split can bind only 1 antibody, exposure to split HLA antigen can lead to development of antibody to this antigen but there is high probability of forming antibody to the other splits of the broad antigen.
For example HLA A9 is a broad antigen that splits into HLA A 23, HLA A24, thus if patient is sensitized to HLA A23 there is high probability of developing antibodies against HLA A24 if exposed to the same sensitizing event.
· Many non -HLA antibodies are formed against released Ag from the graft upon exposure to traumatic events like (ischemia-reperfusion injury and surgery itself), those antibodies were corelated to both active and chronic AMR and eventually worse graft outcome.
· The evidence of the role of non-HLA antibodies in rejection comes from rejection in HLA identically transplant couples.
· Non-HLA antibodies are either directed against:
o Polymorphic allogenic antigens in graft (different epitope matching), as we just do HLA typing..
o Autoantibodies: directed against own Ag (as endothelial Ag- anti-endothelial cell antibodies) after their exposure to traumatic event, ischemia which expose certain self antigens and break self tolerance, disturbed graft microcirculation.
sensitizing events which stimulate both de-novo DSA and non-DSA antibodies formation not essentially major events as re-transplant or blood transfusion. it can be just viral infection or even response to vaccination as COVID 19 vaccine.
Non DSA appear in sensitised patients who have exposure to pregnancy and transfusion or previous transplant
Non DSA appearance post transplant may related to patients non adherence to his drug
Effect of non- DSA on short term predict AMR and long term predict poor graft function
These are associated with poor graft outcome in both short and long term .There is increase incidence of proteinuria and ABMR .
Those who did not revieve ATG have worse prognosis
-Non-HLA antibodies are associated with antibody-mediated rejection and C4d deposition in the absence of circulating donor-specific HLA antibodies.
-Non-HLA antibodies in transplantation can be directed against either polymorphic or nonallelic proteins.
– The development of antibodies against nonpolymorphic targets may be due to upregulation during inflammation, in response to transplantation, or when proteins are exposed to the immune system during injury. It is thought that the intragraft microenvironment or rejection may break humoral tolerance to autoantigens .
-Non-HLA DSA is associated with a greater rate of cellular rejection, lower graft function, and failed renal transplants.
– Non-HLA antibodies binding to airway epithelial cells were detected in lung transplant patients with chronic rejection, bronchiolitis obliterans syndrome (BOS), but not in patients without BOS
-Endothelial cell-binding IgM and IgG were identified using flow cytometry in about half of cardiac transplant patients with transplant coronary artery disease and patients with failed renal allografts.
-Non-HLA antibodies were found at a higher rate in cardiac and renal transplant recipients with or without rejection than in normal or wait-listed subjects, suggesting that these antigens become immunogenic during transplantation.
-Antibodies to MICA and MICB are found in renal where they associate with chronic rejection.
-In renal transplantation, antibodies recognizing glutathione-S-transferase (GST), a cytosolic enzyme that metabolizes toxins, were found in patients experiencing antibody-mediated rejection
-In some experimental studies, non-HLA antibodies do not cause injury.
Referances :
-Nicole M. Valenzuela and Elaine F. Reed. Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury. Methods Mol Biol. 2013; 1034: 10.1007/978-1-62703-493-7_2.
-Zou Y, Stastny P, Susal C, Dohler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med. 2007;357:1293–1300. [PubMed] [Google Scholar]
Still the importance of non-HLA antibodies in kidney transplant is not completely understood, based on evidence from few studies including registry reports which shows that non-HLA antigens associated with increased risk of acute and chronic AMR and accelerated AMR in recipients of renal transplants from HLA-identical siblings.(1,2).
Non-HLA abs could be alloantibodies directed against polymorphic antigens or autoantibodies against recognize self-antigens in the endothelial cell.
the frequency of the non HLA- abs was found higher in recipients with previous history of failed graft or presensitization. Also, organs from deceased donors might have higher levels of non-HLA antibody compared to organs from LD.
AT1R antibodies were IgG1 and IgG3, associated with complement independent endovascular injury and malignant HTN ,its correlated with an increased incidence of AMR and inferior graft survival. Studies shows combination of HLA-abs with AT1R have synergistic effect and increase the risk of AMR and graft loss. Renal biopsy specimens from transplant recipients with AT1R-mediated rejection also had increased tissue factor expression and thrombotic occlusions.
Non-HLA antibodies reported to mediate renal rejection recognize autoantigens expressed by endothelial cells. Brasile et al. were the first to report a patient with pretransplant anti endothelial cell antibodies (AECA) that caused hyperacute rejection and AMR.
Non-HLA antibody directed against self-/non-HLA antigens can lead to positive cross match CDCXM, FXCM with negative DSAs detection by Luminex SAB assay , in case of no previous historic DSA s or clinical history of sensitization so likely its benign and not preclude recipients from transplant with favorable outcome unless its associated with false negative detection of true anti HLA DSAs due to low titer in previously sensitized candidate as it can increase the risk of ABMR due to the cross reactivity with the HLA DSA through immunologic memory recall Historical DSA
Negative DSA pre transplant dose not rule out the possibility of sensitization, always we should ask about historic positive testing. A careful examination of longitudinal SAB screening and prior cross matching results may reveal the presence of a historical DSA and immunologic memory against the donor antigen
There are no existing, clinically validated assays to challenge a latent memory response, determine whether low-titer DSA will remain low, or rapidly increase post transplantation following repeat exposure to the antigen. However, awareness of this potential memory recall response may affect the clinician’s decision to intensify the immunosuppressive regimen and/or post transplantation monitoring strategy.
Mainly non-donor-specific pretransplant HLA class I immunization is an independent risk factor for the development of de novo DSA, ABMR and graft loss.
One study confirm that the pretransplant circulating antibodies against AT1R higher than 30 U in kidney graft recipients consider an independent risk factor for early de novo HLA-DSA detection after transplantation(2).
References:
1-Terasaki PI. Deduction of the fraction of immunologic and non-immunologic failure in cadaver donor transplants. Clin Transpl. 2003:449–52. [PubMed: 15387129]
2. Opelz G. Collaborative Transplant S. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet. 2005; 365:1570–6. [PubMed: 15866311]
3- taeck A, Khadzhynov D, Kleinsteuber A, Lehner L, Duerr M, Budde K, Lachmann N, Halleck F, Staeck O. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. Transpl Immunol. 2020 Dec;63:101333.
4- Cuevas E, Arreola-Guerra JM, Hernández-Méndez EA, Salcedo I, Castelán N, Uribe-Uribe NO, Vilatobá M, Contreras-Saldívar AG, Sánchez-Cedillo AI, Ramírez JB, de Rungs D, Granados J, Morales-Buenrostro LE, Alberú J. Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies. Nephrol Dial Transplant. 2016 Oct;31(10):1738-45.
infections, immunization, blood transfusion can trigger rejection episodes and increase HLA antibodies. A recent study has shown that there is a strong association between the development of infection and increases in both breadth and strength of HLA antibodies [. The increase in the breadth of HLA antibodies was mainly due to expansion of reactivity among other antigens of a cross-reactive group (CREGs). Other studies have shown that in transplant kidney biopsies of acutely rejecting patients with viral infections the presence of plasma cell infiltrates and C4d deposition. The relationship between infection and rise in HLA antibodies is thought to be secondary to the presence of a robust memory B-cell response to the release of pro-inflammatory cytokines.
in conclusion: non DSA anti HLA antibodies have a bad impact on the graft survival
reference:
Krishnan, N. S., Zehnder, D., Daga, S., Lowe, D., Lam, F. T., Kashi, H., Tan, L. C., Imray, C., Hamer, R., Briggs, D., Raymond, N., & Higgins, R. M. (2013). Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation. PloS one, 8(7), e68663. https://doi.org/10.1371/journal.pone.0068663
Thankyou for mentioning the mechanism of their generation and cross reacting CREGS. Can you answer the following questions (and this is for everybody):
1. In clinical practice how are they detected?
2.All agree they are not without bad effects specially on B cell stimulation.
3. Are you going to manage the situation.
1. In clinical practice how are they detected?
-Flowcytometric estimation of blood group antibodies.-Quantification of viral antibodies using LIAISON® analyzer.Using the LIAISON ® analyzer (DiaSorin S.p.A, Saluggia, Italy), Cytomegalovirus (CMV), Varicella Zoster (VZV) and Anti Hepatitis B Surface antigen (Anti-HBsAg) IgG antibodies were quantified from the corresponding serum samples according to manufactures instructions.
–CMV screening and prophylaxis.
2-All agree they are not without bad effects, especially on B cell stimulation.
actually, I didn’t get your point prof.
3. Are you going to manage the situation.
I couldn’t get a proper answer but in my clinical practice we don’t treat it apart from prevention and treatment of infection, avoid blood transfusion as much as possible
***waiting for your comment and guide prof.
References ;Zou Y, Stastny P, Susal C, Dohler B, Opelz G. Antibodies against MICA antigens and kidney-
transplant rejection. N Engl J Med. 2007; 357:1293–300. [PubMed: 17898098]
Brasile L, Rodman E, Shield CF 3rd, Clarke J, Cerilli J. The association of antivascular endothelial
cell antibody with hyperacute rejection: a case report. Surgery. 1986; 99:637–40. [PubMed:
3518110]
Harmer AW, Haskard D, Koffman CG, Welsh KI. Novel antibodies associated with unexplained
loss of renal allografts. Transpl Int. 1990; 3:66–9. [PubMed: 2206221]
Ben please revise the following:non HLA antibodies are not directed to HLA antigens but rather to endothelial cells or anti angiotensin 2receptors.
Third party are antibodies directed to HLA which is not donor specific so they are non donor specific HLA antibodies.
Thanks prof, it is very clear
Anti HlA antibodies both DSA and NDSA can adversely affect graft survival , for NDSA antibodies , they may result from sensitizing events as blood transfusion , pregnancy , infection or inflammation. They may be
1-autoreactive antibodies that give false positive results with crossmatch test but can be diagnosed by SAB
2- natural antibodies : unknown significant
Clinical significant
1- Post transplantation NDSA are associated with higher risk of ABMR and poorer graft survival, the exact mechanism is still poorly understood, it may reflect enhanced immune response status or elevated level of NDSA in contex of acute rejection episode may just be a consequence of ABMR as both DSA and NDSA were found to be elevated during rejection episodes.
Malheiro J, Tafulo S, Dias L, Martins L, Beirão I, Castro-Henriques A. Non-Donor-Specific Anti-HLA Antibodies Have an Adverse Impact in Kidney Graft Outcomes. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/non-donor-specific-anti-hla-antibodies-have-an-adverse-impact-in-kidney-graft-outcomes/. Accessed March 28, 2022
Non DSA antibodies are
antibodies against non Donor antigens
Both DSA and NDSA can be adsorbed by the graft and can be detected in the circulation, in some cases remaining undetected until nephrectomy.
de novo DSA generally of greater strength than de novo NDSA
In addition to DSA, we have observed the consistent induction of diverse, cross-reactive NDSA not only during the post-transplant course but also after graft failure, when immunosuppression is tapered prior to nephrectomy.
since the strong sensitization to NDSA will seriously affected the ability to identify a compatible donor for a future transplant, this reinforce the importance of minimizing HLA mismatches between the donor and the recipient.(1)
Patients with non-donor-specific pretransplant anti-HLA immunization were at a higher risk for
1-developing de novo DSA
2-antibody mediated rejections (ABMR)
3-poorer graft survival and worse graft outcome if not received strong induction with ATG
4- higher decline of the calculated GFR.
5-In elderly patients anti-HLA immunization only had a significant influence on the development of DSA (2).
1- Rebellato LM, Ozawa M, Verbanac KM, Catrou P, Haisch CE, Terasaki PI.
Clinical Transplants 2006, Chapter 18
Clinical and Anti-HLA Antibody Profile of Nine Renal Transplant Recipients with Failed Grafts: Donor-specific and Non-donor-specific Antibody Development.
2- Anja Staeck 1, Dmytro Khadzhynov etal. Influence of pretransplant class I and II non-donor-specific anti-HLA immunization on immunologic outcome and graft survival in kidney transplant recipients. 0.1016/j.trim.2020.101333
Thankyou Dalia for the clear explanation of their effect and the impact on further donor compatibility.
A careful initial compatible search will reduce the CREGS mechanism of their production.
While de novo donor-specific HLA antibodies (dndsas) have a detrimental impact on kidney graft outcome, the clinical significance of de novo non donor-specific antibodies (dnndsas) is more controversial.
20–40%of low-risk, previously non sensitized, kidney recipients will develop
post-transplant de novo donor specific HLA antibodies (dndsas),
leading to late AMR and graft loss in
a significant proportion of patients.
Somestudies have shown that the post-transplant occurrence of dnndsas
in non-sensitized kidney graft recipients
does not have an adverse effect on graft survival
Onthe contrary, other studies have shown that kidney allografted patients who develop dnndsas were at increased risk for graft failure.
Mechanisms for the induction of dnndsas have not yet been clarified.
One research investigated the impact of pretransplant class I and II non-donor-specific anti-HLA on the immunologic outcome and graft survival in kidney transplant patients who had received a kidney transplant.
patients who had received non-donor-specific anti-HLA prior to transplantation had a greater probability of developing de novo DSA antibody-mediated rejections.
A lower death censored graft survival was seen in patients who did not get a non-donor-specific pretransplantation.
The only class I pretransplant HLA immunization, not class II pretransplant HLA immunization, was shown to be a significant independent risk factor for de novo DSA, ABMR, and mortality censored graft loss in a multivariate model.
Another research found that anti-HLA non-DSA antibodies were discovered in 50% of patients who had transplant failure, with DSA antibodies found in about 20% of patients.
Patients with anti-HLA non-DSA antibodies had a poorer graft survival rate.
-F. Cardarelli; M. Pascual; N. Tolkoff-Rubin; F. L. Delmonico; W. Wong; D. A. Schoenfeld; et al.
Well done