ALLOIMMUNE INDIRECT PATHWAY IN ORGAN TRANSPLANTATION

描述：(改编自申请人的摘要)正在进行 大鼠对同种异体抗原免疫反应的本质研究 器官移植的模型，申请者使用了合成的 多肽，它代表多态的、抗原基序，可以 对MHC分子免疫或耐受。T淋巴细胞对此类细胞的识别 多肽是通过抗原呈递抗原的生理途径实现的 寄主的递呈细胞，被称为间接途径 同种异体识别，因为T细胞的其他克隆识别完整的同种异体MHC 分子直接作用于供体细胞。苦参素的口服给药途径 淋巴细胞或合成肽形式的供体抗原可以抑制 以抗原特异性方式发展的TH1免疫反应， 虽然胸腺内注射会产生完全耐受的状态， 通过间接耐受预防急、慢性排斥反应 通往供体II类MHC的途径。申请者假设没有达到 通过间接途径抑制T细胞反应是 慢性排斥过程。他们计划研究人体移植受者， 根据初步结果显示患有慢性肾脏病的患者 同种异体移植排斥反应使T细胞与供者的HLA-DR多肽发生反应。第一, 他们将前瞻性地跟踪一系列移植受者超过一年 确定它们对MHC别肽的反应模式的三年时间 与临床事件有关。假设是应答者会 发展慢性排斥反应，同时保护反应迟钝的患者免受 发展这一进程。其次，它们将产生别肽特异性T细胞 从反应性和低反应性患者的例子中克隆细胞，以 确定人类白细胞抗原限制性模式和T细胞受体基因 表达和细胞因子模式。第三，他们将进行 慢性阻塞性肺疾病患者饲喂相关供体人类白细胞抗原-DR多肽 试图特异性下调免疫反应的排斥反应 通过间接途径，因为这将是初步的可行性研究 开发新的治疗策略，以防止疾病的发展或 阻断慢性排斥反应的进展。

DESCRIPTION: (Adapted from the applicant's abstract) In the process of investigating the nature of the immune response to alloantigens in rat models of organ transplantation, the applicants have employed synthetic peptides, which represent the polymorphic, antigenic motifs which can immunize or tolerize to MHC molecules. T lymphocyte recognition of such peptides is via the physiological pathway of antigen presentation by antigen presenting cells of the host, termed the indirect pathway of allo-recognition, because other clones of T cells recognize intact allo-MHC molecules directly on donor cells. The oral route of administration of donor antigen in the form of lymphocytes or synthetic peptides can suppress the development of the TH1 immune response in an antigen-specific manner, while intra-thymic injection produces a completely tolerant state, preventing acute and chronic rejection by tolerizing via the indirect pathway to donor class II MHC. The applicants hypothesized a failure to suppress T cell responses via the indirect pathway lies at the heart of the chronic rejection process. They plan to study human transplant recipients, based on preliminary results which show that patients having chronic renal allograft rejection have primed T cells to donor HLA-DR peptides. First, they will follow prospectively a series of transplant recipients over a three year period to determine their pattern of response to MHC allopeptides in relation to clinical events. The hypothesis is that responders will develop chronic rejection, while hyporesponsive patients are protected from developing the process. Second, they will generate allopeptide-specific T cell clones from examples of responsive and hyporesponsive patients, to define the HLA-restriction patterns as well as T cell receptor gene expression and cytokine patterns. Third, they will institute experiments of feeding the relevant donor HLA-DR peptides to patients with chronic rejection in an attempt to specifically down-regulate the immune response via the indirect pathway, as this will be an initial feasibility study towards development of new therapeutic strategies to prevent development or interrupt progression of chronic rejection.