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：
8518234
负责人：
Bernhard Josef Hering
金额：
$ 83.9万
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/8518234
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

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

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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.

描述（由适用提供）：拟议的临床前研究的长期目标是开发一种适用于人类胰岛同倍倍替替汀在T1D中使用的临床适用耐受性方案。我们策略的核心部分是用化学交叉接头1-乙基-3-（3-二甲基氨基丙基）-Carbodiimide（ECDI）处理的白细胞递送抗原。给定IV的自身抗原偶联的脾细胞预防和治疗小鼠的自身免疫性。在移植模型中，在-7和+1上给出的ECDI固定供体脾细胞作为对胰岛合金的长期供体特异性耐受性的影响，当与短期雷帕霉素（Rapa）（Rapa）结合使用时，也与小鼠的心脏合金相结合。在多发性硬化症（MS）中自体，胡椒粉耦合摄氏的第一次临床试验最近确定了这种新型耐受性策略的临床可行性。 To test Whether the profound tolerogenic efficiency of alloantigen delivery via ECDI-fixed cells (ADEC) will translate to islet transplantation in nonhuman privates (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.目的＃2：t确定ADEC在诱导的对胰岛同胞同倍形胰岛诱导耐受性RM中的效率，而低记忆和高内存同种异体反应性则用RAPA，STNFR，-IL-6R和LFA3-IG暂时处理。 AIM＃3：检查免疫治疗方案对RM中同种异体移植物的诱导，维护和/或损失的诱导，维持和/或损失的机制的影响。该提案的创新明显在于先发制人使用潜在的，但安全的细胞免疫治疗药作为抗原特异性的，负疫苗。我们的协议针对先天性，异源和自适应直接和间接途径免疫性霍斯托（可以扩展到目标自身免疫性），并且目的地完全避免了广义T和/或B细胞的部署以及CORTALUCTY BLOSSATIONS，以及对NHP中iSlet Alloys持久耐受性的高潜力。拟议的研究将提供有关ADEC和伴随免疫疗法对胰岛合金耐受性诱导的作用的新见解，这是迈向这种抗原特异性耐受策略的临床翻译迈出的关键一步。