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: 6898175
• 负责人: Bernhard Josef Hering
• 金额: $ 56.02万
• 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/6898175
• 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 提高混合造血嵌合方案的安全性和有效性 跨越主要组织相容性 (MHC) 障碍，因此该方法可以 更广泛地应用于诱导受者的强大移植物耐受性 来自活体和尸体捐赠者的胰岛和实体器官同种异体移植物。稳定的 混合供体-宿主造血嵌合总是诱导强健的、终生的、 对供体组织移植物的供体特异性免疫耐受。也能恢复 自身免疫性疾病的自我耐受性。因此这种方法特别 适用于胰岛移植中的耐受诱导。大量 在降低宿主调理方案毒性方面取得的进展 造血细胞同种异体植入和预防 移植物抗宿主病（GVHD）这个棘手的问题现在提供了 应用混合嵌合策略的现实机会 实体器官和细胞移植中的耐受诱导。这是 假设正确使用抗CD40L mAb，最好与 西罗莫司和供体 I；细胞抗原，允许通过初始收缩 同种异体反应性 T 细胞克隆大小、调节性 CD4+CD25+ 细胞的诱导，以及 胸腺内同种异体抵抗的控制-随后稳定的激活 胸腺内混合造血嵌合现象跨部分主要 组织相容性障碍，无需 T 细胞耗竭，胸腺 照射和脾切除术。还假设使用高剂量 造血细胞移植克服了清髓术的需要 和骨髓抑制。在已建立的相关模型中检验这些假设 外周血干细胞移植临床前模型 单倍体相关的非人类灵长类动物，以下具体目标是 建议：具体目标#1：建立稳定的混合造血嵌合状态 在半相合的相关非人灵长类动物外周血接受者中 在短暂免疫抑制的掩护下进行干细胞移植 共刺激阻断。具体目标#2：建立稳定的混合 造血嵌合赋予后续相同供体胰岛的耐受性 皮肤同种异体移植而不损害非人灵长类动物的免疫能力 外周血干细胞移植的接受者。具体目标#3：使用 细胞、分子和遗传分析，以确定潜在的机制 用于建立嵌合现象的方法的作用。这些结果 研究将增加我们对安全性、有效性和 选择性免疫调节方法的潜在机制旨在 最大化半相合相关外周血干的同种异体移植 细胞，从而为混合嵌合体的合理设计提供基础 门诊环境中旨在诱导耐受性的策略 随后使用相同的活体供体胰岛和/或实体器官同种异体移植物。