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，用于人类胰岛同种异体T1D移植。我们的策略的中心组成部分是将抗原输送到用化学交联剂1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide处理的白细胞上。自身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固定的供者脾细胞在第7天和第1天静脉注射，可诱导供者对同种异体胰岛移植物的长期耐受，当与短期雷帕霉素(RapA)联合使用时，也可诱导小鼠同种异体心脏移植物的长期耐受。最近，人类首次对多发性硬化症(MS)进行了自体、多肽偶联CELS的临床试验，证实了这种新的耐受策略的临床可行性。为了测试通过ECDI固定细胞(ADEC)传递同种异体抗原的深刻耐受性是否会转化为非人类灵长类动物(NHP)的胰岛移植，我们将研究以下特定目标：目的1：生产符合预期释放标准的ADEC产品，用于评估在RM的同种异体胰岛移植中的耐受性。目的#2：检测ADEC对RAPA、sTNFR、β-IL-6R和LFA3-Ig短暂处理的低、高记忆同种异体反应性大鼠胰岛移植耐受的影响。目的#3：研究免疫治疗方案对诱导、维持和/或丧失供者对同种异体胰岛移植耐受的潜在机制的影响。这一提议的创新之处在于抢先使用了有效但安全的细胞免疫疗法作为抗原特异性的阴性疫苗。我们的方案针对的是先天的、异种的和适应性的直接和间接途径免疫(并且可以扩展到靶向自身免疫)，并且尽管完全避免了全身性T和/或B细胞耗竭和共刺激阻断，在NHP中诱导对同种异体胰岛移植的持久耐受的潜力很高。这项拟议的研究将为ADEC和伴随的免疫疗法在诱导同种异体胰岛移植耐受中的作用提供新的见解，这是向这种抗原特异性耐受策略临床移植的关键一步。

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.