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

描述（由申请方提供）：拟定临床前研究的长期目标是开发一种临床适用的致耐受性方案，用于T1 D患者的人胰岛同种异体移植。我们的策略的中心组成部分是在用化学交联剂1-乙基-3-（3-二甲基氨基丙基）-碳二亚胺（ECDI）处理的白细胞上递送抗原。IV给予的自身抗原偶联的脾细胞预防和治疗小鼠的自身免疫。在移植模型中，在第-7天和+1天IV给予ECDI固定的供体脾细胞诱导对胰岛同种异体移植物的长期供体特异性耐受，并且当与短期雷帕霉素（RAPA）组合时，也诱导对小鼠心脏同种异体移植物的长期供体特异性耐受。最近，在多发性硬化症（MS）中进行的自体肽偶联受体的首次人体临床试验确立了这种新的致耐受性策略的临床可行性。为了测试通过ECDI固定细胞（ADEC）递送同种异体抗原的显著致耐受性功效是否将转化为非人灵长类动物（NHP）中的胰岛移植，我们将研究以下具体目标：目的#1：制造符合前瞻性定义的放行标准的ADEC产品，用于评价RM中胰岛同种异体移植中的耐受原。目标2：在具有低和高记忆同种异体反应性的RM中，用RAPA、sTNFR、<$-IL-6 R和LFA 3-IG短暂治疗，以确定ADEC诱导胰岛同种异体移植物耐受的功效。目标3：研究免疫方案对诱导、维持和/或丧失RM中供体对胰岛同种异体移植物特异性耐受的机制的影响。该提案的创新之处在于明确地抢先使用有效但安全的细胞免疫治疗剂作为抗原特异性阴性疫苗。我们的方案靶向先天性、异源性和适应性直接和间接途径免疫（并可扩展至靶向自身免疫），尽管完全避免了全身性T和/或B细胞耗竭和共刺激阻断，但在NHP中诱导对胰岛同种异体移植物持久耐受的潜力很高。拟议的研究将提供新的见解ADEC的作用和伴随的免疫疗法诱导胰岛同种异体移植物的耐受性，这是向临床转化的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.