HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

Kawai, Tatsuo; Sachs, David H.; Sykes, Megan; Cosimi, A. Benedict

doi:10.1056/nejmc1213779

Cited by 506 publications

(349 citation statements)

References 5 publications

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“…These studies provide evidence for a role for deletion in the maintenance of allograft tolerance in humans. While we cannot exclude the possibility that donor-reactive clones moved from the circulation into the allograft, this would be inconsistent with protocol biopsies showing no rejection and minimal cellular infiltrates, which are enriched for Foxp3+ cells, in tolerant CKBMT recipients (6, 7). …”

Section: Discussionmentioning

confidence: 89%

“…Deletion of donor-reactive clones in CKBMT recipients was partially explained by global T cell depletion induced by conditioning (6, 7, 12, 13). The initial recovery of T cells in CKBMT recipients is most likely driven by LIP, as most T cells express an effector/memory phenotype in the first 3–6 months post-transplant (12), as observed for rapid LIP (19), which is largely antigen-driven (24, 25).…”

Section: Discussionmentioning

confidence: 99%

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Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients

et al. 2015

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T cell responses to allogeneic major histocompatibility (MHC) antigens present a formidable barrier to organ transplantation, necessitating long-term immunosuppression to minimize rejection. Chronic rejection and drug-induced morbidities are major limitations that could be overcome by allograft tolerance induction. Tolerance was first intentionally induced in humans via combined kidney and bone marrow transplantation (CKBMT), but the mechanisms of tolerance in these patients are incompletely understood. We now establish an assay to identify donor-reactive T cells and test the role of deletion in tolerance after CKBMT. Using high-throughput sequencing of the TCRB chain CDR3 region, we define a fingerprint of the donor-reactive T cell repertoire prior to transplantation and track those clones post-transplant. We observed post-transplant reductions in donor-reactive T cell clones in three tolerant CKBMT patients; such reductions were not observed in a fourth, non-tolerant, CKBMT patient or in two conventional kidney transplant recipients on standard immunosuppressive regimens. T cell repertoire turnover due to lymphocyte-depleting conditioning only partially accounted for the observed reductions in tolerant patients; in fact, conventional transplant recipients showed expansion of circulating donor-reactive clones, despite extensive repertoire turnover. Moreover, loss of donor-reactive T cell clones more closely associated with tolerance induction than in vitro functional assays. Our analysis supports clonal deletion as a mechanism of allograft tolerance in CKBMT patients. The results validate the significance of donor-reactive T cell clones identified pre-transplant by our method, supporting further exploration as a potential biomarker of transplant outcomes.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients

et al. 2015

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“…In our initial clinical trial of tolerance induction for HLA-mismatched kidney allografts, we used the anti-CD2 mAb, MEDI507, chosen because of its unique properties of both T cell depletion and co-stimulatory blockade (7). Although this agent was effective (8, 9), its clinical availability is currently uncertain. Thus we have sought alternative approaches for adding costimulatory blockade to T cell depletion with ATG.…”

Section: Introductionmentioning

confidence: 99%

Use of CTLA4Ig for Induction of Mixed Chimerism and Renal Allograft Tolerance in Nonhuman Primates

Yamada

Ochiai

Bosković

et al. 2014

American Journal of Transplantation

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We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates (NHP). In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4-Igs, Abatacept and Belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, ATG and a one month post-transplant course of cyclosporine (CyA)). Three recipients treated with the Abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the Belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the Belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with Belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance.

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“…As reviewed by Sachs, Kawai, and Sykes, establishing tolerance by inducing mixed chimerism has had success in preclinical and clinical studies and has been the most successfully translated strategy for transplant tolerance to date [66]. This is exemplified by Kawai’s study of end-stage renal disease patients receiving combined bone marrow and kidney transplants [67,68]. Following conditioning, five patients received living related kidneys donated by relatives that were mismatched for one HLA haplotype.…”

Section: Approaches To Transplant Tolerancementioning

confidence: 99%

“…The regimen used for these patients was further modified to include two additional doses of rituximab and studied in five subsequent patients. Three were able to discontinue immunosuppression and were free from rejection at the 3 year mark [68]. With these promising results, this strategy may prove the closest to expanded clinical use.…”

Section: Approaches To Transplant Tolerancementioning

confidence: 99%

Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance

Gracon¹,

Wilkes²

2014

Human Immunology

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Despite significant medical advances since the advent of lung transplantation, improvements in long-term survival have been largely unrealized. Chronic lung allograft dysfunction, in particular obliterative bronchiolitis, is the primary limiting factor. The predominant etiology of obliterative bronchiolitis involves the recipient’s innate and adaptive immune response to the transplanted allograft. Current therapeutic strategies have failed to provide a definitive treatment paradigm to improve long-term outcomes. Inducing immune tolerance is an emerging therapeutic strategy that abrogates allograft rejection, avoids immunosuppression, and improves long-term graft function. The aim of this review is to discuss the key immunologic components of obliterative bronchiolitis, describe the state of establishing immune tolerance in transplantation, and highlight those strategies being evaluated in lung transplantation.

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HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

Cited by 506 publications

References 5 publications

Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients

Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients

Use of CTLA4Ig for Induction of Mixed Chimerism and Renal Allograft Tolerance in Nonhuman Primates

Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance

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