Mixed Chimerism in Haploidentical Non-human Primates

单倍体非人类灵长类动物的混合嵌合现象

• 批准号: 6613829
• 负责人: Bernhard Josef Hering
• 金额: $ 54.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613829
• 关键词: Macaca; antileukocyte isoantibody; artificial immunosuppression; cooperative study; immune tolerance /unresponsiveness; monoclonal antibody; nonhuman therapy evaluation; pancreatic islet transplantation; sirolimus; skin transplantation; stem cell transplantation; tissue mosaicism; transplantation immunology

DESCRIPTION (provided by applicant): The Long-term goal of this project is to improve the safety and efficacy of mixed hematopoietic chimerism protocols across major histocompatibility (MHC) barriers such that this approach can be more widely applied for the induction of robust graft tolerance in recipients of islet and solid organ allografts from living and cadaver donors. Stable mixed donor-host hematopoietic chimerism invariably induces robust, lifelong, donor-specific immunologic tolerance to donor tissue grafts. It also restores self-tolerance in autoimmune disorders. Thus this approach is particularly suitable for tolerance induction in islet transplantation. Considerable progress made in reducing the toxicity of the host conditioning regimens required for allogeneic engraftment of hematopoietic cells and in preventing the formidable problem of graft-versus-host disease (GVHD) now provides realistic opportunities for the application of mixed chimerism strategies for tolerance induction in solid organ and cellular transplantation. It is hypothesized that the correct use of anti-CD40L mAb, preferably combined with sirolimus and donor I;ellular antigen, allows, via initial contraction of the alloreactive T cell clone size, induction of regulatory CD4+CD25+ cells, and control of intrathymic alloresistance--the subsequent activation of stable intrathymic mixed hematopoietic chimerism across partial major histocompatibility barriers without the need for T cell depletion, thymic irradiation, and splenectomy. It is also hypothesized that the use of highdose hematopoietic cell transplantation overcomes the need for myeloablation and myelosuppression. To test these hypotheses in the established relevant preclinical model of peripheral blood stem cell transplantation in haploidentical, related nonhuman primates, the following Specific Aims are proposed: SPECIFIC AIM #1: To establish stable mixed hematopoietic chimerism in haploidentical, related nonhuman primate recipients of peripheral blood stem cell transplants under the cover of transient immunosuppression and costimulatory blockade. SPECIFIC AIM #2: To establish that stable mixed hematopoietic chimerism confers tolerance to subsequent same donor islet and skin allografts without compromising the immunocompetence of nonhuman primate recipients of peripheral blood stem cell transplants. SPECIFIC AIM #3: T o use cellular, molecular, and genetic assays to define the underlying mechanisms of action of the approaches used to establish chimerism. The results of these studies will increase our understanding of the safety, efficacy, and underlying mechanisms of selective immunomodulatory approaches aimed at maximizing alloengraftment of haploidentical, related peripheral blood stem cells, thereby providing a basis for the rational design of mixed chimerism strategies in the outpatient setting for the purpose of inducing tolerance to subsequent same living donor islet and/or solid organ allografts.

描述（由申请人提供）：该项目的长期目标是 提高混合造血嵌合体方案的安全性和功效 在主要的组织相容性（MHC）障碍中，这种方法可以是 更广泛地用于诱导接受者耐受的耐受性耐受性 来自生物和尸体供体的胰岛和坚实的器官。稳定的 混合供体宿主造血嵌合体总是诱导强大的终身 供体特异性免疫耐受性对供体组织移植物。它也还原 自身免疫性疾病的自我耐受性。因此，这种方法特别是 适用于胰岛移植中的耐受性诱导。大量 在降低宿主条件方案的毒性方面取得的进展 造血细胞的同种异体植入所必需的 现在，移植物抗宿主病（GVHD）的严重问题提供了 实现混合嵌合策略的现实机会 固体器官和细胞移植的耐受性诱导。这是 假设正确使用抗CD40L mAb，最好与 西洛里木斯（Sirolimus）和供体I; ellular抗原，允许通过初始收缩 同种反应性T细胞克隆大小，调节性CD4+ CD25+细胞的诱导和 控制胸膜抗抗药性 - 随后的稳定激活 胸膜混合混合造血嵌合体 组织相容性障碍无需T细胞耗竭，胸腺 辐照和脾切除术。还假设使用高点 造血细胞移植超过了骨髓的需求 和骨髓抑制。在已建立的相关性中检验这些假设 外周血干细胞移植的临床前模型 单倍型，相关的非人类灵长类动物，以下具体目的是 提议：特定目的＃1：建立稳定的混合造血嵌合体 在单倍型，相关的非人类灵长类动物接受者中 在瞬态免疫抑制和 co虫封锁。特定目的＃2：确定稳定的混合 造血嵌合体赋予对随后的供体胰岛的容忍度，并 皮肤同种异体移植物而不会损害非人类灵长类动物的免疫能力 外周血干细胞移植的接受者。特定目标＃3：使用 细胞，分子和遗传测定，以定义的基本机制 用于建立嵌合主义的方法的作用。这些结果 研究将提高我们对安全性，功效和 针对选择性免疫调节方法的基本机制 最大化单倍体的，相关的外周血茎 细胞，从而为混合嵌合的合理设计提供了基础 门诊环境中的策略是为了诱发容忍度 随后使用同种供体胰岛和/或固体器官同种异体移植物。