Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

摘要 异种移植长期以来一直被提出作为一种治疗策略，以解决持续的器官短缺 在移植方面。近年来，猪到灵长类动物异种移植的结果有了显着改善 随着猪供体的基因工程和基于共刺激阻断的 免疫抑制，这样翻译到临床似乎触手可及。高度同种异体致敏的患者， 那些因接触外来HLA而产生抗供体抗体的人是最有潜力的 考虑到他们接受同种异体移植的机会减少，然而，在这方面， 异种移植中同种异体致敏作用的影响在猪-异种移植中尚未完全阐明， 灵长类动物模型。我们的初步数据表明，同种异体致敏促进抗体介导的排斥反应 (AMR)在异种肾移植后，并导致早期移植失败。使用来自高血压患者的供体肾脏 工程猪延长异种移植物存活，但不能完全缓解AMR的发展。另外的治疗 因此，需要策略来抑制异种移植后的移植后体液应答， 敏感的接受者。该项目旨在评估新的脱敏和免疫抑制策略， 控制移植后体液反应，促进致敏受体的长期异种移植存活。 我们的总体假设是，在异种移植之前， 通过脱敏和连续靶向B细胞、浆细胞或补体， 移植，是必要的，以控制移植后的体液反应，并改变重建 异种反应性免疫库以有利于长期移植物接受。为了探索这一点，我们提出了3个具体的 目的：具体目的1：我们将定义脱敏（共刺激阻断和蛋白酶体）的作用 抑制剂）在经历肾异种移植的恒河猴中的移植前的作用。具体目标2：我们将 定义针对体液应答下游要素的辅助治疗的影响， 异种移植具体目标3：我们将鉴定异种特异性T和B细胞的功能表型 建立长期无AMR异种移植物存活率同时保留抗病毒/疫苗所需的库 反应这些进展最终将使我们能够在2010年进行首次人体异种移植。 致敏患者测试这种优化的免疫抑制方案。我们的建议涉及许多学术界 以及正在进行的行业合作，如支持信所证明的。该提案的影响 广泛的影响，可能有利于美国公民受终末期肾衰竭或免疫介导的 疾病或感染。

Abstract Xenotransplantation has long been proposed as a therapeutic strategy to address the ongoing organ shortage in transplantation. In recent years, pig-to-primate xenotransplantation outcomes have dramatically improved following advances in the genetic engineering of pig donors and utilization of costimulation blockade-based immunosuppression, such that translation to the clinic appears within reach. Highly allosensitized patients, those who have developed anti-donor antibody as a response to foreign HLA exposure, are potential first candidates for xenotransplantation given their reduced chances of undergoing allotransplantation. However, the impact of allosensitization in the setting of xenotransplantation has not yet been fully elucidated in pig-to- primate models. Our preliminary data suggest that allosensitization promotes antibody-mediated rejection (AMR) following kidney xenotransplantation and leads to early graft failure. Use of donor kidneys from highly engineered pigs prolong xenograft survival yet do not fully alleviate AMR development. Additional therapeutic strategies are thus needed to dampen the post-transplant humoral response following xenotransplantation in sensitized recipients. This project aims to evaluate novel desensitization and immunosuppression strategies to control the post-transplant humoral response and foster long-term xenograft survival in sensitized recipients. Our overarching hypothesis is that both conditioning the host immune response ahead of xenotransplantation through desensitization and continuous targeting of B cells, plasma cells, or complements following transplantation, are necessary to control the post-transplant humoral response and alter the repopulating xenoreactive immune repertoire to favor long-term graft acceptance. To explore this, we propose 3 specific aims: Specific aim 1: We will define the effects of desensitization (costimulation blockade and proteasome inhibitor) pre-transplant in rhesus monkeys undergoing kidney xenotransplantation. Specific aim 2: We will define the impact of adjuvant therapies targeting downstream elements of the humoral response following xenotransplantation. Specific aim 3: We will identify the functional phenotype of xeno-specific T and B cell repertoires required to establish long-term AMR-free xenograft survival while preserving anti-viral/vaccinal response. These advances will ultimately position us to conduct a first-in-human xenokidney transplantation in sensitized patients testing this optimized immunosuppressive regimen. Our proposal involves many academic and industry collaborations that are ongoing as attested by letters of support. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated illnesses or infections.