INTRATHYMIC TRANSPLANTATION TOLERANCE BY MHC PEPTIDES

MHC 肽对胸腺内移植的耐受性

• 批准号: 6373351
• 负责人: Mohamed H Sayegh
• 金额: $ 31.63万
• 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/6373351
• 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（改编自申请人摘要）：同种异体移植排斥反应 这是一个依赖于CD 4 +T细胞的过程。这些T细胞可以识别 同种异体抗原通过两个不同的，但不相互排斥的途径。在 在“直接”途径中，T细胞识别细胞表面的完整allo-MHC分子。 供体抗原呈递细胞（APC）的表面。在“间接”中 途径，T细胞识别加工的同种异体抗原（主要是同种异体抗原）， MHC）由自身APC呈递为肽。越来越多的证据表明， 实验动物和人类支持间接的重要作用， 同种异体识别介导同种异体移植排斥反应。已经 假设这条途径，类似于生理标称 抗原识别途径，可能是重要的发展， 慢性排斥反应的进展，临床上最重要的问题， 器官移植因此，可以说， 对间接同种异体识别的耐受性是导致 慢性排斥支持这些的实验证据 缺乏假设。本提案的目的是研究 间接同种异体识别介导的免疫应答和效应机制 同种异体移植排斥，特别是慢性排斥。调查人员 还将研究抑制间接作用的效果和机制 同种异体识别对排斥过程的发展。上 他们将确定是否用供体启动动物， 衍生的MHC同种异体肽诱导/加速同种异体排斥反应。他们 还将研究是否通过抑制CD 4 +T细胞活化， 间接途径防止急性和慢性排斥反应的发展。 在具体目标2中，研究者将使用已建立的Th 1和Th 2 T细胞， 自我限制以识别和响应供体的细胞克隆 II类MHC同种异体肽，以研究是否过继转移这种 克隆将“促进/增强”（Th 1）或“调节”（Th 2）免疫细胞， 对血管化同种异体移植物的反应。最后，在具体目标3中， 与Laurence A.图尔卡，他们计划 以产生对供体II类MHC具有特异性的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RAG 2敲除小鼠只能通过间接免疫排斥反应来排斥同种异体移植物。 同种识别上述研究对于理解 间接同种识别在介导免疫应答中的作用及其机制 急性和慢性同种异体移植排斥反应。这些研究的结果应该 产生临床相关信息，促进开发新的 诱导供体特异性耐受的策略。