IMMUNE MECHANISMS OF CHRONIC ALLOGRAFT REJECTION

慢性同种异体移植排斥的免疫机制

• 批准号: 2837476
• 负责人: CHARLES B CARPENTER
• 金额: $ 19.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837476
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; antigen presenting cell; chemokine; chronic disease /disorder; clone cells; cytokine; gene expression; heart transplantation; helper T lymphocyte; homologous transplantation; immunocytochemistry; isoantibody; isoantigen; kidney transplantation; laboratory rat; leukocyte activation /transformation; monoclonal antibody; mutant; nucleic acid sequence; pathologic process; polymerase chain reaction; transplant rejection; transplantation immunology

Vascularized organ transplants frequently develop a progressive obliterative vasculopathy, interstitial fibrosis and, in the case of kidneys, glomerulosclerosis, that lead to organ failure within a few years, in spite of continuing immunosuppressive therapy. This 'chronic rejection' process is poorly understood, and although there is clear evidence that T cell recognition of alloantigen plays a key role in initiating early acute rejection, there is little direct evidence that an active alloimmune response is responsible for progression of chronic rejection. In an established rat model of kidney and heart transplants (F344 and LEW strains) in which the sequential morphological and immunohistologic features, with associated cytokine/chemokine gene activation patterns, are well defined, the MHC antigen-driven T cell and antibody responses will be studied. These strains differ only by a class II public antigen. The hypothesis is that an ongoing alloantigen-driven response initiated by T cells primed by the indirect pathway of allorecognition is responsible for mediating the chronic rejection process. The sequences of F344 will be obtained and peptides prepared which represent the difference(s) with LEW MHC class II in order to establish the presence of T cell priming to the indirect pathway during chronic rejection. Preparation of T cell clones for transfer to naive recipients of grafts, and the use of monoclonal antibodies to TCRV/Beta families to block recognition in vivo, will test the significance of priming to immunodominant epitopes in chronic rejection. Tolerance- inducing strategies using synthetic peptides after transplantation will then be applied to interrupt the ongoing process of T cell activation. The hypothesis is supported by preliminary data showing that a single injection of CTLA4Ig to block T cell costimulation via CD28-B7, in addition to preventing chronic rejection if given early, can interrupt progression of chronic rejection when given 8 weeks after transplantation. Further study using antibodies and CTLA4Ig mutants which distinguish between B7-1 and B7-2 pathways should further elucidate approaches to interrupting chronic rejection. The synthetic MHC peptide and costimulatory blockade protocols will be tested for synergistic interaction, and full MHC class I and II strain differences will be subsequently studied. The above studies should provide relevant information for development of novel strategies to prevent and possibly interrupt chronic allograft rejection in clinical transplantation.

血管化的器官移植经常会出现进行性的 闭塞性血管病变、间质纤维化， 肾脏，肾小球硬化，导致器官衰竭，在几个月内， 多年来，尽管持续的免疫抑制治疗。 这是慢性的 拒绝的过程知之甚少，虽然有明确的 有证据表明T细胞对同种异体抗原的识别在 由于早期急性排斥反应的发生，几乎没有直接证据表明， 主动的同种免疫应答是慢性炎症进展的原因， 排斥反应 在已建立的肾脏和心脏移植大鼠模型中， (F344和LEW菌株），其中顺序的形态和 免疫组织学特征，相关细胞因子/趋化因子基因 激活模式，是明确定义的，MHC抗原驱动的T细胞和 将研究抗体应答。 这些菌株的区别仅在于 II公共抗原。 假设是一个持续的同种抗原驱动的 由间接途径引发的T细胞引发的反应 同种异体识别负责介导慢性排斥反应 过程 将获得F344的序列并制备肽 其代表与LEW MHC II类的差异， 建立T细胞启动间接途径的存在， 慢性排斥 制备用于转移至幼稚细胞的T细胞克隆 移植物的接受者，以及抗TCRV/β单克隆抗体的使用 家庭，以阻止识别在体内，将测试的意义 慢性排斥反应中免疫显性表位的启动。 宽容- 移植后使用合成肽的诱导策略将 然后应用于中断正在进行的T细胞活化过程。 这一假设得到了初步数据的支持，初步数据显示， 注射CTLA 4 Ig以阻断通过CD 28-B7的T细胞共刺激， 除了预防慢性排斥反应外，如果早期给予， 慢性排斥进展，8周后给药 移植 使用抗体和CTLA 4 Ig突变体的进一步研究 区分B7-1和B7-2途径的方法应进一步阐明 治疗慢性排斥反应的方法 合成的MHC肽 将测试共刺激阻断方案的协同作用。 相互作用，以及完整的MHC I类和II类菌株差异将是 后来研究。 上述研究应提供相关的 为制定新战略提供信息， 阻断临床移植慢性排斥反应。