Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

摘要 异种移植长期以来一直被认为是解决目前器官短缺的一种治疗策略。 在移植中。近年来，猪到灵长类异种移植的结果有了显著的改善。 猪供体基因工程研究进展及共刺激阻断技术的应用 免疫抑制，这样转换到临床似乎是触手可及的。高度同种异体致敏的患者， 那些已经发展出抗供体抗体作为对外来人类白细胞抗原暴露的反应的人，可能是第一个 考虑到他们接受同种异体移植的机会减少，他们可能会接受异种移植。然而， 同种异体致敏在异种移植环境中的影响尚未在猪到猪之间完全阐明。 灵长类模型。我们的初步数据表明，同种异体致敏促进了抗体介导的排斥反应。 异种肾移植后发生急性心肌梗死(AMR)，并导致早期移植失败。高位供体肾的使用 工程猪延长了异种移植的存活时间，但并不能完全缓解AMR的发展。额外的治疗方法 因此需要采取策略来抑制异种移植后的体液反应。 敏感的接受者。该项目旨在评估新的脱敏和免疫抑制策略以 控制移植后体液反应，促进致敏受者异种移植的长期存活。 我们的主要假设是，在异种移植之前，两者都调节宿主免疫反应 通过脱敏和持续靶向B细胞、浆细胞或补体 移植对于控制移植后的体液反应和改变再填充是必要的。 异种反应性免疫系统有利于移植物的长期接受。为了探索这一点，我们提出了3个具体的 目标：具体目标1：我们将定义脱敏效应(共刺激、阻断和蛋白酶体 抑制物)在进行异种肾移植的恒河猴移植前。具体目标2：我们将 确定针对以下体液反应下游因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 在保留抗病毒/疫苗的同时建立长期无AMR异种移植存活所需的指征 回应。这些进展最终将使我们能够在#年进行首例人类异种肾移植。 测试这种优化的免疫抑制方案的致敏患者。我们的建议涉及许多学术领域 以及正在进行的行业合作，如支持函所证明的那样。这项提议的影响有 可能使受终末期肾功能衰竭或免疫调节影响的美国公民受益的广泛影响 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.