INTRATHYMIC TRANSPLANTATION TOLERANCE BY MHC PEPTIDES

MHC 肽对胸腺内移植的耐受性

• 批准号: 6170293
• 负责人: Mohamed H Sayegh
• 金额: $ 30.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170293
• 关键词: MHC class II antigen; SCID mouse; T cell receptor; T lymphocyte; antigen presentation; cell line; cell transplantation; clone cells; cytokine; genetically modified animals; helper T lymphocyte; histocompatibility; histocompatibility antigens; homologous transplantation; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; passive immunization; transplant rejection

DESCRIPTION (adapted from the applicant's abstract): Allograft rejection is a CD4+T cell dependent process. These T cells can recognize alloantigen via two distinct, yet not mutually exclusive, pathways. In the "direct" pathway, T cells recognize intact allo-MHC molecules on the surface of donor antigen-presenting cells (APCs). In the "indirect" pathway, T cells recognize processed alloantigen (predominantly allo- MHC) presented as peptides by self APCs. Increasing evidence from experimental animals and humans supports a significant role for indirect allorecognition in mediating allograft rejection. It has been hypothesized that this pathway, analogous to the physiologic nominal antigen recognition pathway, may be important in development and progression of chronic rejection, the most important problem in clinical organ transplantation. Therefore, it can be argued that the absence of tolerance to indirect allorecognition is responsible for development of chronic rejection. Definitive experimental evidence supporting these hypotheses is lacking. The purpose of this proposal is to study the role and effector mechanisms of indirect allorecognition in mediating allograft rejection, particularly chronic rejection. The investigators will also study the effects and mechanisms of inhibiting indirect allorecognition on development of the rejection process. In the first specific aim they will determine whether priming animals with donor- derived MHC allopeptides induces/accelerates allograft rejection. They will also study whether inhibiting CD4+T cell activation via the indirect pathway prevents development of acute and chronic rejection. In specific aim 2 the investigators will use established Th1 and Th2 T cell clones which are self-restricted to recognize and respond to donor class II MHC allopeptides to study whether adoptive transfer of such clones will "promote/enhance" (Th1) or "regulate" (Th2) the immune response to vascularized allografts. Finally, in specific aim 3, in collaboration with the laboratory of Dr. Laurence A. Turka, they plan to create a TCR transgenic animal with specificity to donor class II MHC allopeptide presented by self APCs. This animal, when backcrossed onto SCID or RAG2 knockout mice, can only reject an allograft by indirect allorecognition. The above studies are critical to understanding of the contribution and mechanisms of indirect allorecognition in mediating acute and chronic allograft rejection. Results from these studies should yield clinically relevant information facilitating development of novel strategies to induce donor-specific tolerance.

描述(改编自申请人的摘要)：同种异体移植排斥反应 是一个依赖于CD4+T细胞的过程。这些T细胞可以识别 同种异体抗原通过两条截然不同但不相互排斥的途径。在……里面 在“直接”途径中，T细胞识别完整的异基因MHC分子 供体抗原提呈细胞(APC)表面。在“间接”中 途径，T细胞识别处理的同种异体抗原(主要是同种异体抗原) MHC)由自身APC以多肽形式呈现。越来越多的证据来自 实验动物和人类支持间接的重要作用 同种异体识别在调节同种异体移植排斥反应中的作用。一直以来 假设这条通路，类似于生理标称 抗原识别途径，可能在发育和发育中起重要作用 慢性排斥反应的进展--临床最重要的问题 器官移植。因此，可以说，没有 对间接同种异体识别的耐受是导致 慢性排斥。确凿的实验证据支持这些观点 假说是缺乏的。这项建议的目的是研究 和间接同种异体识别在中介中的效应机制 同种异体排斥反应，尤其是慢性排斥反应。调查人员 还将研究间接抑制的效果和机制 对排斥过程发展的异同认识。在第一个 具体目标他们将决定是否给动物注射捐赠者- 衍生的MHC别肽诱导/加速同种异体移植排斥反应。他们 还将研究是否通过抑制CD4+T细胞活化 间接途径可预防急性和慢性排斥反应的发生。 在特定目标2中，研究人员将使用已建立的Th1和Th2 T细胞 自我限制以识别供体并对供体做出反应的细胞克隆 研究II类MHC别肽是否可收养转移此类 克隆人将“促进/增强”(Th1)或“调节”(Th2)免疫 对带血管同种异体移植的反应。最后，在具体目标3中，在 与劳伦斯·A·图尔卡博士的实验室合作，他们计划 建立具有供体II类MHC特异性的TCR转基因动物 由自身APC呈递的别肽。这种动物，当回交到 SCID或RAG2基因敲除小鼠只能通过间接方式排斥同种异体移植 异种认同感。上述研究对于理解 间接同种异体识别在中介中的作用和机制 急性和慢性同种异体移植排斥反应。这些研究的结果应该是 提供与临床相关的信息，促进新药的开发 诱导供者特异性耐受的策略。