Costimulation blockade, chimerism and tolerance across varying degrees of MHC dis

不同程度的 MHC dis 的共刺激阻断、嵌合和耐受

• 批准号: 7632233
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 74.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632233
• 关键词: Acute; Address; Adoptive Immunotherapy; Allografting; Biological Preservation; Bone Marrow Transplantation; Chimerism; Chronic; Classification; Clinical; Competence; Dose; Effectiveness; Foundations; Haplotypes; Hematopoietic; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunosuppressive Agents; Life; Link; Macaca mulatta; Mediating; Modeling; Mus; Natural Killer Cells; Numbers; Organ Transplantation; Outcome; Patient Care; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Pre-Clinical Model; Protocols documentation; Purpose; Reliance; Research Infrastructure; Rodent Model; Skin; Solid; Solutions; T-Lymphocyte; Techniques; Technology; Therapeutic immunosuppression; Toxic effect; Transplant Recipients; Transplantation; Transplantation Tolerance; Treatment Protocols; base; conditioning; genetic pedigree; improved; insight; kidney allograft; nonhuman primate; pre-clinical; research study; response; success

Immune tolerance, the phenomenon by which the allograft is accepted without immunosuppression while preserving the recipient's protective immunity, represents a solution to the problems of acute and chronic rejection and the resulting long-term reliance on toxic immunosuppressive therapies. The significant success of transplantation tolerance studies in rodent models has suggested that similar tolerance-induction techniques involving bone marrow transplant and hematopoietic chimerism could be achieved in preclinical and clinical situations, thus revolutionizing solid organ transplantation. Non-human primate models have a number of important attributes that allow them to serve as critical preclinical models in order to bridge the basic insights gained in mice and the application of these insights to patient care. Among the most prominent of the tolerance induction strategies are CD28/CD40 T cell costimulation blockade and mixed chimerism induction. By taking advantage of our ability to induce chimerism using mobilized peripheral blood stem cells from living Rhesus macaque donors, we propose to perform a systematic analysis of impact of a costimulation blockade and chimerism-based tolerance induction strategy in transplant pairs having varying degrees of MHC disparity. These studies also are focused on understanding the immune consequences of transplant, specifically on evaluating the anti-donor response and the preservation of protective immunity in the peritransplant period. The unifying purpose of our proposal is to develop clinically applicable protocols for the induction of tolerance to solid organ allografts while preserving immune competence in the transplant recipient. Specifically, the aims in this project will address 1) the effectiveness of a CD28/CD40 costimulation-blockade-based chimerism/tolerance induction protocol on transplants displaying varying degrees of MHC matching between the donor and recipient, 2) the necessary components of the immunomodulatory strategy for chimerism and tolerance induction, and 3) the efficacy of inhibiting Natural Killer cell-mediated alloreactivity in order to decrease the need for recipient conditioning and/or donor peripheral blood stem cells to promote tolerance across MHC barriers. We believe the ability to induce stable donor chimerism and immune tolerance in this transplant setting would have a large impact on the outcome of transplantation, and holds the promise of relieving many transplant recipients from the requirement for complicated life-long immunosuppressive regimens and their attendant toxicities.

免疫耐受是指移植物在无免疫抑制的情况下被接受， 保护接受者的保护性免疫力，代表了急性和慢性疾病的解决方案。 排斥反应以及由此导致的对毒性免疫抑制疗法的长期依赖。了重大成就 在啮齿动物模型中的移植耐受性研究表明，类似的耐受诱导 涉及骨髓移植和造血嵌合体的技术可以在临床前 和临床情况，从而彻底改变实体器官移植。非人类灵长类动物模型有一个 许多重要的属性，使他们能够作为关键的临床前模型，以桥接 在小鼠中获得的基本见解以及这些见解在患者护理中的应用。的最 免疫耐受诱导策略的主要方法是CD 28/CD 40 T细胞共刺激阻断和混合免疫耐受。 嵌合诱导通过利用我们的能力，诱导嵌合体使用动员外周血 从活的恒河猴供体中提取干细胞，我们建议进行系统的分析， 共刺激阻断和基于嵌合的耐受诱导策略 MHC差异的程度。这些研究也集中在了解免疫后果， 移植，特别是在评估抗供体反应和保护性免疫的保存， 移植前后时期。我们提案的统一目的是制定临床适用的方案， 诱导对实体器官同种异体移植物的耐受，同时保留移植物中的免疫能力 收件人。具体而言，本项目的目标将解决1）CD 28/CD 40的有效性 基于共刺激-阻断的嵌合/耐受诱导方案对表现出不同的移植物进行诱导 供体和受体之间的MHC匹配程度，2） 嵌合和耐受诱导的免疫调节策略，和3）抑制天然免疫调节剂的功效。 杀伤细胞介导的同种异体反应性，以减少对受体调节和/或供体 外周血干细胞，以促进跨MHC屏障的耐受性。我们相信诱导稳定的 在这种移植环境中，供体嵌合体和免疫耐受将对结果产生很大影响 移植，并有望减轻许多移植受者的要求， 复杂的终身免疫抑制方案及其伴随的毒性。