Induction of Donor-Specific Tolerance: Is This Achievable?
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Abstract:
To the Editor,
The final goal of transplant physicians is the induction of donor-specific tolerance (DST), in which the host permanently accepts the graft, but immunity against other antigens is maintained. There have been reports of successful induction of DST in rodent models. However, the majority of studies have focused primarily on the inhibition of co-stimulatory signals that regulate the activation of T cells, and belatacept, a high-affinity variant of CTLA4-IgG, is the only biological drug that has been applied to human organ transplantation [1]. Antigen-presenting cells (APCs) are activated by the innate immune response, and mature APCs are the key regulators of rejection through activation of the acquired immune response. Therefore, the control of APC maturation is the key step in induction of DST in the field of organ transplantation. Previously, we reported induction of DST through control of APC maturation [2]. However, we were not able to delineate the underlying mechanisms, nor apply the methods to other models of transplantation.
Recently, Jung et al. [3] reported a significant contribution where they showed successful induction of DST through the control of APC maturation. They developed a way to maintain APCs in a semi-arrested state by administration of an antibody ligating a particular epitope on intercellular adhesion molecule 1 (ICAM-1). Signaling through ICAM-1 is important for the activation of APCs. They evaluated the effect of semi-arrested APCs on xenogeneic grafts in humanized mice and non-human primates. Thus, they provided a feasible method that may assist the realization of the DST concept. Further work will likely be connected to clinical trials.
However, care should be taken when interpreting these results and applying them directly to humans. The study was performed not on 'organs' but, rather, on a 'group of cells', because 'group of cells' induces a milder immune response, as compared to that against an organ. Moreover, a thorough method for screening various microorganisms in xenogeneic species has not yet been developed. Therefore, the safety issue remains to be resolved. Despite these limitations, this study provides new insight and will help overcome the problem of non-specific immunosuppression. Furthermore, this study may facilitate control of immune responses more meticulously and safely by providing a method of controlling the immune response at the site of interest.Keywords:
Belatacept
BACKGROUND: The establishment of tolerance protocols would avoid the debilitating effects of chronic immunosuppression and render Vascularized Composite Allotransplantation (VCA) a routine procedure. We investigated graft survival and tolerance induction using co-stimulation blockade with either abatacept or the higher-affinity equivalent drug belatacept. METHODS: Fully MHC- and gender mismatched MGH miniature swine underwent heterotopic hind-limb transplantation. Recipient animals received a short course (30 days) of tacrolimus monotherapy, +/- donor BM infusion, and CTLA4Ig (either abatacept or belatacept). Tacrolimus only and untreated animals served as controls. Recipients were assessed for: chimerism (SRY-gene PCR analysis), alloreactivity against donor antigens (in vitro CFSE-MLR assays), and donor-specific antibodies (DSA) production (serum flow cytometry analysis). Robust immune tolerance in vivo was assessed by skin grafting. Tolerance maintenance upon allograft removal was tested by CFSE-MLR. RESULTS: Both regimens using abatacept or belatacept plus donor BM infusion resulted in indefinite graft survival (>200 days). While only transient peripheral chimerism was observed, stable micro-chimerism in various graft and recipient tissues was achieved. An increase in intragraft Tregs was seen in tolerant animals as compared to controls. Tolerant animals displayed unresponsiveness to donor but not to third party allogeneic controls in CFSE-MLRs. Donor-matched skin grafts were accepted while third party grafts where quickly rejected indicating donor-specific tolerance. No signs of chronic rejection or donor-specific antibodies were seen in tolerant recipients in either group (abatacept vs belatacept). Graft removal, however, was associated with loss of donor-unresponsiveness 5 weeks post-graftectomy. CONCLUSIONS: Combined costimulation blockade and donor BM cell infusion induced robust donor-specific immune tolerance in a translational fully MHC-mismatched hind limb transplant model.
Belatacept
Abatacept
Immunosuppression
Allotransplantation
Mixed lymphocyte reaction
Allorecognition
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Immunosuppression
Belatacept
Solid organ
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The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo-belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept-based regimen with 3.03% using it in over 50% of their patients. The use of T-cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1-year post-transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long-term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.
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Abatacept
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Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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In June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen.Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase 3 trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Overall, there seemed to be an improvement in cardiometabolic parameters in patients treated with belatacept compared with cyclosporine. There was a trend toward higher rates of early rejection episodes in patients treated with belatacept. One safety issue that must be considered when using belatacept is the potential for increased risk of posttransplant lymphoproliferative disease, especially in Epstein-Barr virus-seronegative recipients or patients treated with lymphocyte-depleting agents.Belatacept is the first new agent available in kidney transplant that may achieve the goal of improved long-term renal function.
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Abatacept
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In June 2011, the US Food and Drug Administration approved belatacept for the prophylaxis of organ rejection in adult kidney transplant recipients. This review discusses the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase III trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. However, the rate of acute rejection was higher in belatacept-treated patients compared with cyclosporine. Specifically, there was a higher incidence of Banff type II rejections in patients treated with belatacept. Despite the higher Banff grade, rejections on belatacept were not associated with other factors associated with poor outcomes, such as the development of donor-specific antibodies or reduced estimated glomerular filtration rate. One safety issue that must be considered when using belatacept is the potential for increased risk of post-transplant lymphoproliferative disease. There were more cases of post-transplant lymphoproliferative disease in belatacept-treated patients, especially in recipients seronegative for Epstein-Barr virus or patients treated with lymphocyte-depleting agents. Therefore, belatacept can be recommended for use in Epstein-Barr virus antibody-positive recipients.
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Abatacept
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Background. Costimulatory blockade with belatacept has demonstrated long-term benefits in renal transplantation, but de novo use in liver transplant recipients has resulted in increased rejection, graft loss, and death. However, belatacept conversion as a calcineurin inhibitor (CNI) avoidance strategy has not been studied and may be of benefit in liver transplantation where CNI-induced renal dysfunction and toxicity are barriers to improved outcomes. Methods. Using clinical data extracted from our institutional medical record, we report on 8 patients who underwent kidney after liver transplantation and were treated with belatacept-based immunosuppression and transient CNI therapy. Results. All patients tolerated belatacept therapy without any patient deaths or graft losses. No episodes of rejection, de novo donor-specific antibody formation, or major systemic infections were observed, and all patients demonstrated preserved liver and excellent renal allograft function. Patients received belatacept for a median duration of 13.2 mo, and at a median follow-up of 15.9 mo post–kidney transplant, 6 of 8 patients continued on belatacept with 3 completely off and 3 poised to transition off CNI. Conclusions. These findings are the first evidence that in liver transplant recipients requiring subsequent kidney transplantation, belatacept-based therapy can potentially facilitate CNI-free maintenance immunosuppression. This supports the possibility of belatacept conversion in stand-alone liver transplant recipients as a viable method of CNI avoidance.
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Immunosuppression
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Induction of immune tolerance is characterized by high efficiency,low toxicity and economic advantages,and immune tolerance has very important significance in organ transplantation.In the establishment of immune tolerance,dendritic cells (DCs) play the key roles such as clonal deletion or clonal anerge,expressing t-cell inhibiting factors,activating helper T cells electively and inducing regulatory T cells,especially CD4 + CD25 + regulatory T cells,etc.Similarly,CD4 + CD25 + regulatory T cells whose primary target point is dendritic cell also have various functions such as affecting dendritic cells'maturing,restraining dendritic cells'antigen presentation to T cells,inhibiting the activation of T cells in non-specific ways and inducing immune tolerance.Current research shows,dendritic cells and CD4 + CD25 + regulatory T cells regard each other as target point and work synergetically.Here we mainly discuss the function and interaction of dendritic cells and CD4 + CD25 + regulatory T cells in the immune tolerance.
Key words:
Dendirtic cell; CD4+ CD25+ regulatory T cell; Organ transplantation; Immune tolerance
Regulatory T cell
Peripheral tolerance
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Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept-based regimen, transitioned to a CNI–free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI-associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA. Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept-based regimen, transitioned to a CNI–free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI-associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA.
Belatacept
Immunosuppression
Regimen
Allotransplantation
Abatacept
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