ALLOIMMUNE INDIRECT PATHWAY IN ORGAN TRANSPLANTATION

描述：（改编自申请人摘要） 探讨大鼠对同种异体抗原免疫应答的性质 在器官移植模型中，申请人采用了合成的 肽，其代表多态性抗原基序， 免疫或耐受MHC分子。 T淋巴细胞识别这种 多肽是通过抗原呈递的生理途径 宿主的呈递细胞，称为间接途径， 同种异体识别，因为其他T细胞克隆识别完整的同种异体MHC 分子直接作用在供体细胞上。 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TH 1免疫应答， 虽然胸腺内注射产生完全耐受状态， 通过间接免疫耐受预防急性和慢性排斥反应 第二类MHC的供体。 申请人假设未能 通过间接途径抑制T细胞反应是 慢性排斥反应 他们计划研究人类移植受体， 根据初步结果显示， 同种异体移植排斥已经使T细胞对供体HLA-DR肽产生了反应。 第一、 他们将前瞻性地跟踪一系列的移植接受者， 用三年的时间来确定他们对MHC同种异体肽的反应模式 与临床事件有关。 假设是，响应者将 发生慢性排斥反应，而低反应患者则受到保护， 发展过程。 第二，它们将产生同种异体肽特异性T 来自反应性和低反应性患者的细胞克隆， 确定HLA限制性模式以及T细胞受体基因 表达和细胞因子模式。 第三，他们将进行实验， 将相关供体HLA-DR肽喂给慢性 排斥反应，试图特异性下调免疫反应， 通过间接途径，因为这将是一个初步的可行性研究 开发新的治疗策略，以防止发展或 阻止慢性排斥反应的发展。

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.