Pig-to-Monkey Islet Xenotransplantation

 描述(由申请人提供)：成功的人类胰岛移植已经证明了胰岛细胞替代疗法在1型糖尿病中的潜力。临床前概念验证研究表明，在猴子体内进行猪胰岛移植后，糖尿病的逆转时间延长，这表明异种移植可以提供所需的无限胰岛供应，使细胞替代疗法在糖尿病治疗中变得广泛可用和有效。然而，该领域的批评性综述得出结论，异种胰岛移植的免疫反应是强烈的，目前还没有一致有效和临床适用的预防异种胰岛移植排斥反应的方案。因此，释放猪胰岛移植的巨大潜力的唯一最重要的障碍是对异种胰岛移植的免疫。我们的数据表明食蟹猴(CM)门脉内移植的猪胰岛具有直接和间接的特异性。也越来越明显的是，B细胞在启动T细胞对异种胰岛移植的反应中起着重要作用，并潜在地增强了移植物浸润性T细胞的效应功能。我们假设，通过预防排斥反应，可以延长无药物猪到CM异种胰岛移植的存活时间：i)阻断B细胞以启动异种T细胞的反应和记忆生成；ii)删除具有间接特异性的抗供体T细胞并扩大调节性B和T细胞；以及iii)删除直接途径MHC I类限制的抗供体CD8+T细胞或干扰其激活和效应功能。为了验证这一假设，我们将追求三个目标：目标1：克隆生产用于CM异种胰岛移植的转基因猪。目的#2：观察抗原特异性免疫疗法和转基因成年猪胰岛在一过性免疫抑制条件下延长异种胰岛移植存活时间的效果。目的#3：确定免疫治疗方案对CM中供者特异性异种胰岛移植物诱导、维持和/或丧失无反应性的机制的影响。这些研究将为新的异种抗原特异性细胞免疫疗法和B细胞靶向疗法在猪供体到非人类灵长类胰岛异种移植中的作用和机制提供重要的见解。

 DESCRIPTION (provided by applicant): Successful human islet transplants have demonstrated the potential of islet cell replacement therapies in type 1 diabetes. Preclinical proof-of-concept studies showing prolonged diabetes reversal after porcine islet transplantation in monkeys suggest that xenografts could provide the unlimited supply of islets required for cell replacement therapies to become widely available and impactful in diabetes care. However, critical reviews of the field conclude that the immune response to islet xenografts is vigorous and that a consistently effective and clinically applicable regimen for preventing islet xenograft rejection is not yet available. Thus, the single most significant remaining barrier to unlocking th profound potential of pig islet transplantation is the immunity to islet xenografts. Our data indicates that intraportal porcine islet xenografts in cynomolgus monkeys (CM) activate T cells with both direct and indirect specificity. It is also becoming increasingly apparent that B cells ae instrumental in priming the T cell response to islet xenografts and potentially enhancing the effector functions of graft-infiltrating T cells. We hypothesize that drug-free pig-to-CM islet xenograft survival can be prolonged with a rejection prophylaxis that i) blocks B cells to prime xenogeneic T cell responses and memory generation, ii) deletes anti-donor T cells with indirect specificity and expands regulatory B and T cells, and iii) deletes direct pathway MHC class I-restricted anti-donor CD8+ T cells or interferes with their activation and effector function. To tet this hypothesis, we will pursue three AIMS: Aim #1: To clonally produce genetically modified pigs for use in islet xenotransplantation in CM. AIM #2: To examine the efficacy of antigen-specific immunotherapies and genetically modified adult pig islets in prolonging drug-free islet xenograft survival in CM given transient immunosuppression. AIM #3: To determine the effects of the immunotherapeutic protocol on mechanisms underlying the induction, maintenance, and/or loss of donor-specific unresponsiveness to islet xenografts in CM. The proposed studies will provide important insights into the efficacy and mechanisms of novel xenoantigen-specific cellular immunotherapeutics and B cell-targeting therapies in genetically modifies porcine donor-to-nonhuman primate islet xenotransplantation.