Belatacept in kidney transplantation and its limitations
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Introduction: Since the approval of belatacept in 2011 for use in the setting of de novo kidney transplantation, this CD80/86 – CD28 co-stimulation blocker has been shown to be a valuable treatment option for maintenance immunosuppression.Areas covered: In this setting, belatacept has been associated with superior glomerular filtration rate as compared to calcineurin inhibitor-based treatments because of the absence of nephrotoxicity. Additionally, belatacept avoids the cardiovascular side effects (e.g. hypertension and dyslipidemia) caused by a CNI-based-regimen. Nevertheless, belatacept-treated recipients have a higher rate of acute rejections and a higher risk of lymphoproliferative disorders.Expert opinion: Data suggest a benefit from early conversion vs. late conversion of belatacept in a conversion setting following CNI-related toxicity. Randomized studies are currently comparing belatacept to tacrolimus, instead of cyclosporine, as was done in the Belatacept Evaluation of Nephroprotection and Efficacy as a First-line Immunosuppression Trial (BENEFIT). The benefits and limitations of belatacept seem to be the same when tacrolimus is used instead of cyclosporine.Finally, we also report in this review on the immunological data available so far that explain belatacept's limitations and the higher rate of acute rejection. The goal is to find the optimal immunosuppressive strategy to improve efficacy and safety at post-transplantation.Keywords:
Belatacept
Immunosuppression
Abatacept
CIITA
Combined antigen-specific T cell receptor stimulation and costimulation are needed for complete T cell activation. Belatacept and abatacept are nondepleting fusion proteins blocking CD28/B7 costimulation, whereas siplizumab is a depleting antiCD2 immunoglobulin G1 monoclonal antibody targeting CD2/CD58 costimulation. Herein, the effect of siplizumab combination therapy with abatacept or belatacept on T cell alloreactivity in mixed lymphocyte reactions was investigated. In contrast to monotherapy, the combination of siplizumab with belatacept or abatacept induced near-complete suppression of T cell proliferation and increased the potency of siplizumab-mediated T cell inhibition. Furthermore, dual targeting of CD2 and CD28 costimulation enhanced the selective depletion of memory T cells compared with monotherapy. Although siplizumab monotherapy leads to significant regulatory T cell enrichment, high doses of cytotoxic T-lymphocyte-associated antigen 4 and a human IgG1 Fc fragment in the combination therapy reduced this effect. These results support the clinical evaluation of dual costimulation blockade, combining siplizumab with abatacept or belatacept, for the prophylaxis of organ transplant rejection and improvement of long-term outcomes following transplantation. Ongoing investigative research will elucidate when other forms of siplizumab-based dual costimulatory blockade may be able to induce similarly strong inhibition of T cell activation although still allowing for enrichment of regulatory T cells.
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Cyclosporine and tacrolimus are potent inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes. In renal transplant patients tacrolimus is more powerful in preventing severe and refractory rejections, even when compared with the new cyclosporine microemulsion formulation. Both drugs are equally nephrotoxic, but tacrolimus induces less hypertension and less pronounced hyperlipidaemia. Especially in some categories of patients, a higher incidence of de-novo diabetes mellitus is seen with tacrolimus therapy.
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Abstract Belatacept is a novel agent that prevents CD28 signaling and inhibits T‐cell activation by costimulation blockade. It was developed from abatacept (CTLA‐4 Ig), the first recombinant immunoglobulin fusion protein that contains extracellular portion of CTLA‐4, and the Fc domain of IgG. Early studies have shown that belatacept recipients show comparable patient and graft survival, superior renal function and renal biopsy data compared with cyclo‐sporine‐treated patients. Newer biologic agents such as belatacept offer the promise of real change—due to their lack of mechanism‐related toxic effects—and help monitor drug administration, thereby improving compliance. Belatacept is a potential option for maintenance biologic therapy without a calcineurin inhibitor, accompanied by excellent mid‐term results with yet unknown long‐term safety and efficacy. The increased rate of TCMR and possibly central nervous system post‐transplantation lymphoproliferative disorder are worrisome and need to be further elucidated.
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Vascularized composite allotransplantation (VCA) has emerged as a viable limb replacement strategy for selected patients with upper limb amputation. However, allograft rejection has been seen in essentially all reported VCA recipients indicating a requirement for substantial immunosuppressive therapy. Calcineurin inhibitors have served as the centerpiece agent in all reported cases, and CNI-associated complications associated with the broad therapeutic effects and side effects of calcineurin inhibitors have been similarly common. Recently, belatacept has been approved as a calcineurin inhibitor replacement in kidney transplantation, but to date, its use in VCA has not been reported. Herein, we report on the case of a hand transplant recipient who developed recurrent acute rejection with alloantibody formation and concomitant calcineurin inhibitor nephrotoxicity, all of which resolved upon conversion from a maintenance regimen of tacrolimus, mycophenolate mofetil and steroids to belatacept and sirolimus. This case indicates that belatacept may be a reasonable maintenance immunosuppressive alternative for use in VCA, providing sufficient prophylaxis from rejection with a reduced side effect profile, the latter being particularly relevant for nonlife threatening conditions typically treated by VCA. Vascularized composite allotransplantation (VCA) has emerged as a viable limb replacement strategy for selected patients with upper limb amputation. However, allograft rejection has been seen in essentially all reported VCA recipients indicating a requirement for substantial immunosuppressive therapy. Calcineurin inhibitors have served as the centerpiece agent in all reported cases, and CNI-associated complications associated with the broad therapeutic effects and side effects of calcineurin inhibitors have been similarly common. Recently, belatacept has been approved as a calcineurin inhibitor replacement in kidney transplantation, but to date, its use in VCA has not been reported. Herein, we report on the case of a hand transplant recipient who developed recurrent acute rejection with alloantibody formation and concomitant calcineurin inhibitor nephrotoxicity, all of which resolved upon conversion from a maintenance regimen of tacrolimus, mycophenolate mofetil and steroids to belatacept and sirolimus. This case indicates that belatacept may be a reasonable maintenance immunosuppressive alternative for use in VCA, providing sufficient prophylaxis from rejection with a reduced side effect profile, the latter being particularly relevant for nonlife threatening conditions typically treated by VCA.
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Abatacept
CD80
Immunosuppression
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Belatacept is a novel immunosuppressive agent that inhibits T-cell activation by blocking CD28 signaling pa- thway. It was developed based on abatacept (CTLA-4Ig), the fi rst recombinant immunoglobulin fusion protein which contains extracellular part of CTLA-4 molecule and Fc domain of IgG. First clinical trials have shown the comparable patient and graft survival in group of kidney recipients with belatacept-based maintenance im- munosuppressive therapy versus Cyclosporin A-based therapy. Advantages observed with belatacept include superior glomerular fi ltration rate and improved cardiovascular risk pro fi le. Belatacept is a potential option for maintenance immunosuppressive therapy without calcineurin inhibitors. Concerns associated with belatacept use are higher rates of acute cellular rejection episodes and post-transplant lymphoproliferative disorder cases.
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Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.
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