Alloantigen Delivery Via ECDI-Fixed Cells For Tolerance To Monkey Islet Grafts

描述（由申请人提供）：拟议的临床前研究的长期目标是开发一种临床适用的耐受性方案，用于T1D患者的人类胰岛异体移植。我们策略的核心部分是将抗原递送到经化学交联剂1-乙基-3-（3-二甲氨基丙基）-碳二亚胺（ECDI）处理过的白细胞上。自体抗原偶联脾细胞静脉注射预防和治疗小鼠自身免疫。在移植模型中，ecdi固定的供体脾细胞在第7天和第1天静脉注射可诱导供体对胰岛移植物的长期特异性耐受，当与短期雷帕霉素（RAPA）联合使用时，也可诱导小鼠对心脏移植物的长期特异性耐受。一项针对多发性硬化症（MS）的自体肽偶联细胞的首次人体临床试验最近证实了这种新的耐受性策略的临床可行性。为了测试通过ecdi固定细胞（ADEC）递送的同种异体抗原的耐受性是否会转化为非人灵长类动物（NHP）的胰岛移植，我们将研究以下具体目标：目标#1：制造符合预期定义的释放标准的ADEC产品，以评估在RM的胰岛移植中的耐受性。目的2：确定ADEC诱导低记忆和高记忆异体反应性RM对胰岛移植物耐受的效果，RAPA、sTNFR、¿-IL-6R和LFA3-Ig短暂治疗。目的3：研究免疫治疗方案对RM患者诱导、维持和/或丧失供体特异性胰岛移植耐受的机制的影响。这一建议的创新之处在于，首先使用有效而安全的细胞免疫疗法作为抗原特异性阴性疫苗。我们的方案针对先天、异源和适应性直接和间接途径免疫（并可扩展到靶向自身免疫），尽管完全避免了全身性T细胞和/或B细胞消耗和共刺激阻断，但在NHP中诱导对胰岛同种异体移植物的持久耐受性方面具有很高的潜力。拟议的研究将为ADEC和伴随的免疫治疗在诱导胰岛异体移植耐受中的作用提供新的见解，这是临床翻译这种抗原特异性耐受策略的关键一步。

DESCRIPTION (provided by applicant): The long-term goal of the proposed preclinical studies is to develop a clinically applicable tolerogenic protocol for use in human islet allotransplantatin in T1D. The central component of our strategy is the delivery of antigens on leukocytes treated with the chemical cross linker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI). Autoantigen-coupled splenocytes given IV prevent and treat autoimmunity in mice. In transplant models, ECDI-fixed donor splenocytes given IV on days -7 and +1 - as induce long-term donor-specific tolerance to islet allografts, and when combined with short-term rapamycin (RAPA), also to heart allografts in mice. A first-in-human clinical trial of autologous, peptide-coupled cels in multiple sclerosis (MS) recently established the clinical feasibility of this novel tolerogenic strategy. To test whether the profound tolerogenic efficacy of alloantigen delivery via ECDI-fixed cells (ADEC) will translate to islet transplantation in nonhuman primates (NHP), we will study the following specific aims: AIM #1: To manufacture ADEC products meeting prospectively defined release criteria for evaluation as tolerogens in islet allotransplantation in RM. AIM #2: T determine the efficacy of ADEC in inducing tolerance to islet allografts in RM with low and high memory alloreactivity transiently treated with RAPA, sTNFR, ¿-IL-6R, and LFA3-Ig. AIM #3: To examine the effects of the immunotherapeutic protocol on mechanisms underlying the induction, maintenance, and/or loss of donor-specific tolerance to islet allografts in RM. The innovation of this proposal lies expressly in the preemptive use of potent, yet safe, cellular immunotherapeutics as antigen-specific, negative vaccines. Our protocol targets innate, heterologous, and adaptive direct and indirect pathway immunity (and can be extended to target autoimmunity) and has, despite complete avoidance of generalized T and/or B cell depletion and costimulation blockade, a high potential for inducing durable tolerance to islet allografts in NHP. The proposed studies will provide novel insights into the role of ADEC and concomitant immunotherapy for tolerance induction to islet allografts, a critical step toward clinical translaton of this antigen-specific tolerance strategy.