Biopsy Findings:

• The glomerulus has patent capillary loops with thickened basement membranes at H&E Light Microscopy. 
• The mesangial regions are mildly expanded by an increase in cells and matrix at H&E Light Microscopy .
• Transplant glomerulopathy with prominent reduplication of the basement membrane at Electron microscopy .
• The peritubular capillaries are dilated and contain lymphocytes, the peritubular capillaries show diffuse positivity for C4d deposition by immunohistochemical staining.(PAS Staining & Immunoperoxidase).
• Histological diagnosis: Transplant Glomerulopathy with C4d deposition …chronic AMR.

Diagnosis:
Chronic AMR 

• History of AMR.
• Partial reversibility despite of adequate therapy. SCr jumped from 130 to 250 µmol/L, so 92.3% increment from the baseline and improved by 66.6% in regards to Pre-Treatment level(250 to 170 µmol/L).
• Histological diagnosis in support of CHRONIC AMR.
• C4d in chronic allograft showing area of parenchymal scarring and diffusely positive reaction in interstitial capillaries.“Prognostically, the presence o f C4d was associated with inferior allograft survival compared with DSA or histopathology alone.” Sapir-Pichhadze et al (Canada) Kidney Int 87: 182, 2015

Management:
1/ To date, there are no approved effective treatments for chronic active ABMR, and it remains a major challenge in the field of transplantation.
      REVIEW article Front. Pharmacol., 15 April 2021 | https://doi.org/10.3389/fphar.2021.651222
              Therapies for Chronic Allograft Rejection
                    Min Young Kim and Daniel C. Brennan

2/ One small retrospective study from Taiwan showed that aggressive treatment which included double-filtration plasmapheresis and one or more of the followings: rituximab, intravenous immunoglobulin (IVIG), antithymocyte globulin, bortezomib, or methylprednisolone pulse therapy, especially at the early stage of chronic active ABMR, was associated with better survival than those who received supportive treatment alone (Chiu et al., 2020). 
       REVIEW article Front. Pharmacol., 15 April 2021 | https://doi.org/10.3389/fphar.2021.651222 
             Therapies for Chronic Allograft Rejection
            Min Young Kim and Daniel C. Brennan

3/ Conventional Immunosuppressive Therapy
The differentiation of B cells into LLPCs and the production of high-affinity antibodies are completed with the help of Tfh cells in the germinal center reaction (Wallin, 2018). Effective Tfh cell suppression is crucial to prevent the development of dnDSA. However, conventional immunosuppressive therapies are not thoroughly effective at limiting Tfh cells. 

• Cano-Romero et al. evaluated the effects of induction therapy on circulating Tfh (Cano-Romero et al., 2019). Thymoglobulin significantly depleted circulating Tfh but circulating Tfh recovered within 6 months.
• Basiliximab did not affect the elimination of circulating Tfh (Cano-Romero et al., 2019). 
• Moreover, in a study by Danger et al., thymoglobulin and calcineurin inhibitors (CNIs) were associated with a decreased total circulating Tfh cells but activated circulating Tfh cells increased (Danger et al., 2019). 
• Corticosteroids did not affect circulating Tfh cell distribution (Danger et al., 2019). Although Tfh cell is dependent on nuclear factor of activated T (NFAT) signaling, Tfh cells appear only to be partially inhibited by CNIs and are still able to help B cells to differentiate into plasma cell producing antibodies (Laguna-Goya et al., 2019). 
• In one study, tacrolimus had a minimal inhibitory effect on Tfh cell generation and could only partially prevented Tfh cell activation in vitro (de Graav et al., 2017). 
• Cyclosporin has a 2.7 times higher incidence of dnDSA development than tacrolimus, suggesting a weaker effect on Tfh cells than tacrolimus (Wiebe et al., 2017). 
• Sirolimus, an mTOR inhibitor, may suppress the number of circulating Tfh cells more efficiently than tacrolimus, but sirolimus is more likely to be associated with the development of dnDSA development than tacrolimus (Laguna-Goya et al., 2019). 
• However, subtherapeutic immunosuppression from nonadherence or reduction of immunosuppressive agents is the main cause of chronic active ABMR although rejection reactions are not fully controlled by the conventional immunosuppressive therapies. Therefore, optimizing baseline immunosuppression and enhancing drug compliance should be a priority.

4/ Plasma Exchange and Intravenous Immunoglobulin

• The mainstays of active ABMR treatment are plasma exchange (PE) and IVIG (Schinstock et al., 2020). However, studies for the effects of PE and IVIG have not supported their use in patients with chronic active ABMR. Although plasma exchange can reduce levels of plasma antibodies and graft injury, it is a transient effect (Ionescu and Urschel, 2019). 
• Plasma exchange may require a combination of treatments that inhibit the formation of dnDSA, particularly class II dnDSA, by newly matured plasma cells and long-lived plasma cells (Velidedeoglu et al., 2018; Ionescu and Urschel, 2019).
• The effects of IVIG appear to be on both innate and adaptive immune systems. It can suppress various innate immune cells such as dendritic cells, monocytes, macrophages, neutrophils, and NK cells. It can also neutralize the active complement component and regulate B cell function, plasma cells, Treg cells and effector T cells, and proliferative cytokines (Galeotti et al., 2017).
• Cooper et al. reported that high-dose IVIG eliminated class I antibodies more than class II antibodies and did not link to stabilization of graft function in recipients with chronic graft dysfunction, including chronic active ABMR (Cooper et al., 2014). Whereas in a study by Redfield et al., IVIG and steroids were associated with better graft survival in 123 patients with chronic active ABMR (Redfield et al., 2016). 
• A recently published study described that IVIG and methylprednisolone could reduce the loss of renal function decline in more than 60% of patients with chronic active ABMR with a progressive decline in eGFR (Sablik et al., 2019). 

5/ Anti-CD20 Monoclonal Antibody
Rituximab, a chimeric monoclonal antibody against CD20, eliminates B cells and memory B cells, which leads to depleting allospecific antibodies and anamnestic response (Zhang, 2018). 

• In general, rituximab does not appear to efficiently improve the results of ABMR, although it may have some benefits in active ABMR (Roberts et al., 2012; Macklin et al., 2017). 
• In a multicenter randomized controlled trial for acute ABMR (RITUX-ERAH trial), 38 patients receiving rituximab or placebo were evaluated 1 year after transplantation (Sautenet et al., 2016). The study did not demonstrate additional effects of rituximab in combination with PE, IVIG, and corticosteroids for acute ABMR (Sautenet et al., 2016). Moreover, infectious complications and gastrointestinal disorders occurred more frequently in patients receiving rituximab than in placebo (Sautenet et al., 2016). 
• In the 7-years outcomes of the RITUX-ERAH trial, there was no long-term benefit of rituximab (Bailly et al., 2020).
• Chung et al. reported that the use of IVIG and rituximab increased graft survival in patients with chronic active AMBR (Chung et al., 2014). 
• However, most studies evaluating the effects of rituximab on chronic ABMR or chronic active ABMR failed to demonstrate the efficacy of rituximab on graft outcomes. 
• Piñeiro et al. retrospectively evaluated data of 62 patients with chronic active ABMR. Treatment with rituximab, IVIG, and PE was not associated with the improvement of graft survival and increased the incidence of severe infectious complications compared to the control (Piñeiro et al., 2018). 
• Bachelet et al. retrospectively compared 21 patients receiving two doses of rituximab, four doses of IVIG, and corticosteroids with the untreated control group of 10 patients (Bachelet et al., 2015). At 24 months post-biopsy, graft survival was 47 and 40% in the treated and the untreated group (p = 0.69) and the incidence of adverse events were higher in the treated group (Bachelet et al., 2015). 
• Recently, in a multicenter, randomized placebo-controlled trial, the efficacy and safety of rituximab combined with IVIG were evaluated in patients with chronic ABMR, including chronic active ABMR. Among 25 patients, 13 patients received IVIG (4 doses of 0.5 g/kg) and rituximab (375 mg/m2). There were no significant differences between the treatment and placebo groups in the estimated GFR, proteinuria, 1-year Banff score, and DSA levels (Moreso et al., 2018). 
• Whereas, in a prospective study of 20 pediatric patients with chronic ABMR, treatment consisting of IVIG and rituximab was associated with improvement or stabilization of eGFR, and this response lasted for 24 months. The presence of TG significantly lowered the effectiveness of IVIG and rituximab (Billing et al., 2012).
• In addition, Kahwaji et al. reported that patients with microvascular inflammation might benefit from IVIG and rituximab treatment in the presence of TG (Kahwaji et al., 2014). These results suggest that the treatment may be effective in the early stages of chronic active ABMR. However, the effect of rituximab in chronic active ABMR cannot be defined because IVIG and rituximab were administered together in previous studies. In addition, since the studies published so far are heterogeneous in drug dosage and combination, the number of treatment cycles, and patients, more studies for rituximab are needed.
• Obinutuzumab is a type 2 anti-CD20 antibody and may deplete B cells more than rituximab (Ionescu and Urschel, 2019; Redfield et al., 2019). Recently, Redfield et al. reported that obinutuzumab combined with IVIG potently depleted B cells in hypersensitized patients with ESRD awaiting transplantation. However, there was no clinically meaningful reduction in anti-HLA antibodies (Redfield et al., 2019). The relevance of these findings for the use of obinutuzumab for the treatment of chronic AMR is unclear.

6/ Proteasome Inhibitor
Bortezomib is the selective inhibitor of the 26S proteasome and induces cell death of short- and long-lived plasma cells by accumulating unfolded proteins (Neubert et al., 2008). It was thought to lead to the suppression of the production of dnDSA. 

• The Mayo group showed that bortezomib eliminated DSA-producing plasma cells and PE could enhance DSA removal in sensitized renal transplant recipients (Diwan et al., 2011). 
• In another study, combination therapy with bortezomib, rituximab, and PE reduced DSA levels, and it was associated with improved GFR in patients with early or late acute ABMR (Walsh et al., 2011). 
• Eskandary et al. conducted a randomized, placebo-controlled trial with bortezomib in 44 patients with late ABMR (BORTEJECT trial) (Eskandary et al., 2018b). Bortezomib was administered in two cycles of four doses each to 21 patients. The study failed to demonstrate the efficacy of bortezomib in the prevention of GFR loss, graft survival, histologic or molecular rejection phenotypes, and reduction in DSA (Eskandary et al., 2018b). Moreover, bortezomib increased gastrointestinal and hematologic toxicity (Eskandary et al., 2018b). 
• In a study by Philogene et al., bortezomib reduced HLA class I antibody more effectively than class II antibody (Philogene et al., 2014).
• In addition, Kwun et al. demonstrated that bortezomib-induced plasma cell depletion induced germinal center B cell and Tfh cell expansion in the lymph nodes. This humoral compensation was associated with the generation of new antibody-producing cells and a failure of DSA depletion (Kwun et al., 2017). Furthermore, despite PC depletion, the stability of DSA may occur due to new generation of plasma cells from GC memory B cells, new plasma cells generation due to proliferation within a bone marrow precursor plasma cell population, or reverse differentiation of the LLPC population (Woodle et al., 2017). 
• To date, findings of studies using bortezomib have been inconsistent. This may be caused by the small number of patients enrolled in the studies or differences in drugs used in combination with bortezomib, or because it simply is not effective. A randomized trial is being conducted to evaluate the efficacy of bortezomib in chronic ABMR patients (NCT02201576), and the results may help determine how to use bortezomib in chronic ABMR patients.

Carfilzomib, an irreversible proteasome inhibitor, as opposed to the reversible proteasome inhibitor bortezomib, has a short half-life and less off-target effects, which may have favorable safety compared to bortezomib (Woodle et al., 2020). 

• Ensor et al. reported that carfilzomib in combination with PE and IVIG significantly lowered DSA IgG mean-fluorescence intensity (MFI) and DSA C1q MFI in 10 of 14 lung transplant recipients (Ensor et al., 2017). 
• A recent prospective, nonrandomized trial described that carfilzomib had an acceptable safety and toxicity profile and depleted bone marrow plasma cells and anti-HLA antibodies in highly HLA-sensitized KT candidates (Tremblay et al., 2020). However, antibody levels returned to baseline between days 81 and 141 due to the rebound of the antibody (Tremblay et al., 2020). 
• Woodle et al. suggested that the resistance of plasma cells to carfilzomib may be caused by structural changes of proteasome and immune proteasome formation (Woodle et al., 2020). In addition, carfilzomib-resistant bone marrow plasma cells had low sensitivity to the proteasome inhibitors carfilzomib and bortezomib, whereas they had enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914 (Woodle et al., 2020). 
• In a study by Li et al., ONX 0914 depleted the numbers of B and plasma cells and suppressed the production of DSA in rats that received KT (Li et al., 2018). Identifying mechanisms for the resistance of proteasome inhibitors and targeting them may have the potential to improve transplant outcomes.

7/ Complement-Based Therapy
The complex of anti-HLA DSA and alloantigen activates the classical pathway of the complement system by binding to C1q (Tatapudi and Montgomery, 2019; Bhalla et al., 2020). The binding of C1q activates C1r and C1s, which subsequently cleaves C4 to C4a and C4b, and eventually, this process produces anaphylatoxins of the C3a and C5a and C5b9 membrane attack complexes (Tatapudi and Montgomery, 2019; Bhalla et al., 2020). 

Eculizumab is a humanized monoclonal antibody that blocks the cleavage of C5 into C5a and C5b (Bhalla et al., 2020). C1 esterase inhibitor (CI-INH) inhibits the complement proteases C1r and C1r (Tatapudi and Montgomery, 2019). These complement inhibitors have been used in the prevention and treatment of ABMR. 

• Eculizumab showed the potential to have meaningful positive effects on preventing acute ABMR and improving graft survival in living- and deceased-donor KT recipients (Glotz et al., 2019; Marks et al., 2019). 
• However, eculizumab therapy did not prevent chronic ABMR in recipients with persistently high DSA (Cornell et al., 2015). 
• In KT recipients with de novo DSA MFI >1100 and a 20% reduction in eGFR during the 12 months prior to enrollment, eculizumab therapy appeared to have the ability to stabilize renal function, but the expression of endothelial cell-associated transcripts predicting acute humoral injury was not reduced (Kulkarni et al., 2017). 
• In an observational retrospective study by Schinstock et al., eculizumab therapy reduced the rate of early active ABMR over a 6.8-years follow-up period in highly sensitive recipients, but this did not lead to a decrease in the rate of chronic active ABMR rate or improvement in graft survival (Schinstock et al., 2019). 
• In studies published so far, eculizumab appears to prevent early ABMR in highly sensitive KT recipients during the period of administration, but this does not seem to lead to changes in long-term outcomes. For that reason, it is thought that C5 blockade by eculizumab may activate upstream complement factors, like the anaphylatoxin C3a, and triggering chronic injury and inflammation. Sublytic levels of the membrane attack complex also might cause endothelial cell activation. Furthermore, complement-independent mechanisms might contribute to endothelial damage (Bhalla et al., 2020).
• In previous studies, the use of C1 INH for acute ABMR improved renal function and reduction in TG (Montgomery et al., 2016; Viglietti et al., 2016).
• In late antibody-mediated kidney allograft rejection, anti-C1s monoclonal antibody BIVV009 inhibited the complement pathway, but there was no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function in 5-weeks follow-up biopsies (Eskandary et al., 2018a). However, studies on C1-INH or C1s monoclonal antibodies are too small and heterogenous to define their effectiveness. 

8/ IL-6 Inhibitor
IL-6 acts as a key mediator in the innate immune response and adaptive immunity, and the role of IL-6 in allograft rejection has attracted attention. IL-6 stimulates the production of IL-21 in naive T cells, leading to differentiation into Tfh cells with CXCR5, IL-21, and transcription factor Bcl-6. Naive B cells drawn to the germinal center by CXCR5+ Tfh cells differentiate into plasmablasts capable of producing large amounts of IL-6. Together with IL-21, IL-6 induces plasmablasts to differentiate into LLPCs. In addition, IL-6 plays an important role in shaping T cell immunity, especially increasing Tfh cells and inhibiting regulatory T cells. 

• The production of IL-6 by binding of DSA to alloantigen on graft endothelium can stimulate intimal proliferation and obliterative vasculopathy, likely resulting in manifestations of chronic ABMR (Jordan et al., 2017). Therefore, blockade of IL-6 may inhibit Tfh cell activity, upregulate Treg cell, and reduce the production of plasmablast and DSA. In addition, it may prevent intimal proliferation and obliterative vasculopathy by IL-6 produced in endothelial cells (Jordan et al., 2017). 
• Recently, Shin et al. showed that tocilizumab, an anti–IL-6 receptor monoclonal antibody, reduced total IgG and IgG1-3 and anti-HLA-total IgG and IgG3 levels in patients with chronic ABMR (Shin et al., 2020). 
• Choi et al. evaluated the efficacy of tocilizumab in 36 patients with chronic ABMR and TG who failed standard of care treatment with IVIg and rituximab with or without plasma exchange. At the time of chronic ABMR diagnosis, 31 (86.1%) of 36 patients had class II HLA-DSAs. Tocilizumab significantly reduced DSAs and stabilized renal function. Graft survival and patient survival rates were 80 and 91% at 6 years (Choi et al., 2017). When tocilizumab was stopped, two patients developed mild ABMR detected on a for-cause biopsy at 1 year, suggesting the possibility of rebound IL-6–IL-6R signaling (Choi et al., 2017). 
• In contrast, Massat et al. evaluated the efficacy of tocilizumab in nine patients with ABMR, including six patients with chronic active ABMR, resistant to apheresis, rituximab, and intravenous immunoglobulins. Tocilizumab had no significant effect on graft survival and renal function at 1-year follow-up (Massat et al., 2020). 
• In another report, the efficacy of tocilizumab therapy was described in 10 patients with chronic active ABMR. The slope of decline in eGFR was unchanged and microvascular inflammation score or Molecular Microscope Diagnostic System (MMDx) ABMR scores was not improved at 1-year follow-up (Kumar et al., 2020). 
• A phase four RCT was designed to evaluate the efficacy of tocilizumab in KT recipients with chronic active ABMR (NCT04561986), but it is not yet recruiting. The results of this study may clarify whether tocilizumab is useful for the treatment of chronic active ABMR in kidney transplant patients.

A similar antibody, clazakizumab, is a humanized monoclonal antibody directed against the IL-6 molecule itself rather than the IL-6 receptor. 

• A randomized, double-blind, placebo-controlled, parallel-group phase two trial was conducted to evaluate the safety and efficacy of clazakizumab in 20 patients with late active or chronic active ABMR >365 days post-transplantation (Doberer et al., 2020). Clazakizumab 25 mg or placebo was administered via subcutaneous injection every 4-weeks for 12 weeks, followed by a 40-weeks open-label extension where all participants received clazakizumab. Clazakizumab therapy significantly reduced DSA and showed a potentially beneficial effect on ABMR activity and renal function. Serious infectious events developed in five patients and complications of diverticular disease occurred in two patients (Doberer et al., 2021). 
• Jordan et al. performed an open-label, single-arm phase I/II study to evaluate the safety and tolerability of clazakizumab in 10 patients with chronic ABMR (NCT 03380377) (Jordan et al., 2020). Clazakizumab 25 mg was administered monthly for 12 months, followed by bimonthly infusions. Five patients underwent 18 months of therapy and two patients were withdrawn due to graft failure and at the request of a patient. After 18 months of follow-up, eight patients showed stabilization of renal function and reductions in mean DSA relative intensity scores (Jordan et al., 2020). 
• Currently, a randomized, double-blind, parallel-group, placebo-controlled, phase three trial using clazakizumab for treatment of chronic active ABMR is underway (NCT03744910). Clazakizumab 12.5 mg or placebo will be administered monthly for up to 65 months in 350 patients with chronic active ABMR.

9/ Anti-CD38 Monoclonal Antibody
Daratumumab is a human IgG1 monoclonal antibody targeting CD38, a transmembrane glycoprotein expressed on the surface of many immune cells, including plasma cells, plasmablasts, regulatory T cells, regulatory B cells, and natural killer cells (Krejcik et al., 2016; Kwun et al., 2019). 

• In a recent study, daratumumab therapy significantly reduced anti-HLA DSAs in a non-human primate (NHP) model and a heart/kidney transplant recipient with refractory ABMR and a highly sensitized heart transplant candidate, suggesting the potential of daratumumab as a therapeutic strategy. However, the rapid rebound of DSA and TCMR was observed in NHPs (Kwun et al., 2019). 
• In the study by Krejcik et al., daratumumab activated and expanded cytotoxic T-cells and decreased CD38-expressing immunosuppressive regulatory T and B cells in patients with multiple myeloma (Krejcik et al., 2016). 
• Viola et al. demonstrated that daratumumab therapy decreased the count of total NK cells, but it activated CD38-negative NK cells and enhanced expression of CD80/CD86 T-cell costimulatory molecules on monocytes in patients with multiple myeloma. The T cell population was activated and increased through the binding of CD28 on T cells and CD80/86 on monocytes (Viola et al., 2021). 
• In contrast, Doberer et al. reported the efficacy of daratumumab in a KT recipient with chronic active ABMR and smoldering myeloma. Daratumumab therapy with a 9-months course depleted plasma cells in the bone marrow and blood and NK cells in blood and graft tissue. Donor specific antibodies disappeared in serum. Microcirculation inflammation and molecular AMR activity were improved at a 3-months follow-up biopsy. Subclinical borderline rejection with focal high-grade tubulitis and mild interstitial infiltrates was identified at a follow-up biopsy after 3 months, but no molecular signatures of T-cell–mediated rejection were present and the count of circulating regulatory T cell was not reduced (Doberer et al., 2021). 

10/ Combination Therapy
The various immunosuppression protocols to date are unable to completely reduce DSA titers, prevent a rebound in antibody production, or significantly improve graft survival, particularly in chronic active ABMR. The 2019 expert consensus of the Transplantation Society working group recommends optimizing conventional immunosuppressive agents and supportive therapies in chronic active ABMR patients with existing DSA or dnDSA because of the poor outcomes and adverse events of IVIG, PE, and/or rituximab (Schinstock et al., 2020).

• The combination of targeting LLPCs and effective B cell depletion may be a promising approach in chronic active ABMR (Figure 1).
• Leibler et al. demonstrated that belatacept, a human fusion protein combining the extracellular portion of a CTLA-4 immunoglobulin (CTLA-4-Ig), could bind to CD80 and CD86, and prevent the interaction with CD28 in Tfh cells and limit plasmablast differentiation, production of antibody, especially IgG2 and IgG4, and prevent activation of Tfh cells in KT recipients (Leibler et al., 2018).
• In a study by La Murag et al., selective CD28 blockade sparing CTLA-4 led to superior inhibition of Tfh cells, GC, and DSA responses compared to CTLA-4-Ig (La Muraglia et al., 2020). 
• The non-depleting anti-CD40 antibody, iscalimab, inhibited GC formation and prolonged kidney allograft survival without depleting B cells in NHP (Cordoba et al., 2015). These results suggest the potential therapeutic utility of costimulation blockade in preventing the development of dnDSA and subsequent antibody-mediated graft injury (Cordoba et al., 2015).
• Burghuber et al. evaluated the combination of costimulation blockades, with belatacept and anti-CD40 mAb, and bortezomib in a sensitized non-human primate KT model. This combination therapy significantly diminished bone marrow PCs, Tfh cells, and memory B cell proliferation and prolonged graft survival compared to control animals. However, it was associated with significant infectious complications and drug toxicity (Burghuber et al., 2019). 
• In another study, the combination of carfilzomib and belatacept lowered DSAs, bone marrow PCs, and Tfh cells and improved graft survival in highly sensitized NHP KT recipients (Ezekian et al., 2019). Infectious complications or other toxicity were not identified. However, ABMR developed from rebound of the humoral response (Ezekian et al., 2019). In the only human study of this combination, Jain et al. reported that bortezomib therapy with belatacept reduced DSA and reversed ABMR in 6 KT recipients (Jain et al., 2020).
• In an NHP model, lulizumab, a selective CD 28 blocker, in combination with carfilzomib significantly reduced DSA, Tfh cells, and proliferating B cells in the lymph nodes in allosensitized NHPs. The combination therapy lowered the ABMR score and prolonged graft survival. Furthermore, lulizumab preserved the Treg cell population during desensitization. However, all desensitized animals eventually developed ABMR and graft failure (Schroder et al., 2020). 
• In one animal study, CD28+ memory T cells lost CD28 expression after transplantation, which may be associated with resistance to CTLA4-Ig or selective CD 28 blockade (Mathews et al., 2017). Daratumumab, which targetsCD38, may be used in combination with co-stimulatory blockade agents. However, combination therapy with daratumumab may require simultaneous consideration of modulating the activation of cytotoxic T cells and reduction of regulatory T and B cells.
• Besides combination therapy targeting B cells, cytokine inhibitors, such as anti- IL-6, anti-IL-21, or anti-BAFF, may be combined with co-stimulatory blockade agents. Zhao et al. suggested the combination of co-stimulatory molecule blockade and IL-6 blockade may lead to better graft survival (Zhao et al., 2012). 
• Another study showed that blockade of the IL-21 receptor had the ability to inhibit the differentiation of B cells to antibody-producing plasmablasts (de Leur et al., 2017). The use of belimumab, a BAFF inhibitor, showed a trend to reduce naïve B cells, circulating plasmablasts, and memory B cells in adult KT recipients (Banham et al., 2018).
• However, it is not yet possible to determine whether combination therapy with co-stimulatory blockade agents and B-cell targeting therapy or cytokine inhibitor is superior to current immunosuppressive therapy in terms of safety, efficacy, and cost.