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显示，在猴子中进行猪胰岛移植后，糖尿病逆转时间延长，这表明异种移植物可以提供细胞替代疗法所需的无限胰岛供应，从而在糖尿病护理中广泛使用并产生影响。然而，该领域的评论得出结论，对胰岛异种移植物的免疫应答是强烈的，并且还没有一种持续有效且临床适用的预防胰岛异种移植物排斥反应的方案。因此，释放猪胰岛移植的巨大潜力的唯一最重要的剩余障碍是对胰岛异种移植物的免疫。我们的数据表明，门静脉内猪胰岛异种移植在食蟹猴（CM）激活T细胞的直接和间接的特异性。越来越明显的是，B细胞有助于引发T细胞对胰岛异种移植物的应答，并可能增强移植物浸润T细胞的效应功能。我们假设，无药物的猪-CM胰岛异种移植物存活可以通过以下排斥预防来延长：i）阻断B细胞以引发异种T细胞应答和记忆产生，ii）删除具有间接特异性的抗供体T细胞并扩增调节性B和T细胞，以及iii）删除直接途径MHC I类限制性抗供体CD 8 + T细胞或干扰其活化和效应功能。为了泰特这一假设，我们将追求三个目标：目标#1：克隆生产用于CM胰岛异种移植的转基因猪。目标2：在给予短暂免疫抑制的CM中，检查抗原特异性免疫疗法和转基因成年猪胰岛在延长无药物胰岛异种移植物存活率方面的疗效。目标3：确定免疫方案对CM中胰岛异种移植物供体特异性无反应性诱导、维持和/或丧失机制的影响。这些研究将为新型异种抗原特异性细胞免疫治疗和B细胞靶向治疗在转基因猪供体-非人灵长类动物胰岛异种移植中的疗效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.