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

通过 ECDI 固定细胞递送同种异体抗原以耐受猴胰岛移植物

基本信息

批准号：
8400970
负责人：
Bernhard Josef Hering
金额：
$ 86.94万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8400970
关键词：
Adverse effects Alloantigen Antigens Autoantigens Autoimmunity Autologous B-Lymphocytes CD58 Antigens Carbodiimides Cells Chemicals Chronic Clinical Clinical Trials Clonal Anergy Coupled Diabetic Angiopathies Dose Evaluation Genomics Goals Human Hypoglycemia Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Leukocytes Lymphocyte Function Macaca mulatta Maintenance Memory Modeling Monkeys Multiple Sclerosis Mus Natural Immunity Pathway interactions Patients Peptides Peripheral Blood Mononuclear Cell Phenotype Pre-Clinical Model Proteomics Protocols documentation Regulatory T-Lymphocyte Role Safety Sirolimus Splenocyte T memory cell T-Lymphocyte Testing Tolerogen Translating Translations Transplantation Vaccines allotransplant anergy base cell fixing clinically relevant cost diabetes mellitus therapy diabetic heart allograft immunoregulation innovation insight islet islet allograft isoimmunity meetings nonhuman primate novel preclinical study prevent sample fixation

项目摘要

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. PUBLIC HEALTH RELEVANCE: Human islet allotransplantation restores insulin independence and near normoglycemia, protects from severe hypoglycemia and slows the progression of microvascular complications in those people with type 1 diabetes (T1D). The numerous undesirable side effects and the high costs of chronic immunosuppression limit the applicability of islet transplants. To overcome this limitation, the goal of this proposal is to develop in a pre clinical model of T1D (diabetic non-human primates) tolerogenic protocol(s) for use in human islet allotransplantation in T1D.

描述（由申请人提供）：拟议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 中的人胰岛同种异体移植素。给予自身抗原偶联的脾细胞化学交联剂 1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺 (ECDI)。 IV 预防和治疗小鼠的自身免疫性在移植模型中，ECDI 固定的供体脾细胞在第 -7 天和 +1 天进行 IV 注射，并与短期雷帕霉素 (RAPA) 联合使用，可诱导对胰岛同种异体移植物的长期供体特异性耐受。），也适用于小鼠心脏同种异体移植，最近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证实了这种新颖的临床可行性。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功效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：生产符合 ADEC 的产品。前瞻性定义的评估 RM 胰岛同种异体移植耐受原的释放标准 AIM #2：T 确定 ADEC 在诱导胰岛同种异体移植耐受中的功效。具有低和高记忆同种异体反应性的 RM 暂时用 RAPA、sTNFR、¿ -IL-6R 和 LFA3-Ig 目标#3：检查免疫治疗方案对 RM 中胰岛同种异体移植物供体特异性耐受的诱导、维持和/或丧失机制的影响。明确在于先发制人地使用有效但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性、异源性和适应性直接和间接途径免疫（并且可以扩展到）。尽管完全避免了普遍的 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的持久耐受的潜力很大。拟议的研究将为 ADEC 和伴随免疫治疗的作用提供新的见解。对于胰岛同种异体移植物的耐受诱导，这是这种抗原特异性耐受策略临床转化的关键一步。公共健康相关性：人胰岛同种异体移植可恢复胰岛素独立性和接近正常血糖，防止 1 型糖尿病 (T1D) 患者发生严重低血糖，并减缓微血管并发症的进展。许多不良副作用和慢性免疫抑制的高成本限制了这一治疗的进展。为了克服这一限制，本提案的目标是开发胰岛移植的预应用。 T1D（糖尿病非人类灵长类动物）耐受方案的临床模型，用于 T1D 人类胰岛同种异体移植。