GENETIC CONTROL OF HLA CLASS I ALLOANTIBODY RESPONSES

这项提案的目标是定义分子和 控制人产生人类白细胞抗原能力的细胞机制 针对I类组织相容抗原的抗体反应。我们的 最终目标将是为开始 制定创新战略，最大限度地减少或消除 一种体液的人类白细胞抗原反应。这些调查基于这样一个假设，即 免疫调节主要是通过经典机制来决定的。 免疫反应(Ir)基因，主要由 宿主人类白细胞抗原II类抗原与外源人类白细胞抗原异构肽的结合和呈递 至CD4+T淋巴细胞(辅助细胞)。人类白细胞抗原同种异体抗体的形成 通过这些被激活的T细胞之间的协同作用而启动 淋巴细胞与B淋巴细胞协同，具有适当的 免疫球蛋白受体和ir基因产物。 这项提议有三个具体目标。第一种方法是将 人工合成的人类白细胞抗原II类抗原限制性酶切图谱 代表两个主要基因多态结构域的人类白细胞抗原I类多肽 人类白细胞抗原家族，即人类白细胞抗原A2和人类白细胞抗原B7。直接多肽结合 对活细胞的分析将使用分析流 细胞学。第二个目标将是确定这些ir基因是否 体内产生人类白细胞抗原同种异体抗体的能力 以及这些因素是否导致慢性血管病变 同种异体移植，最终导致移植失败。与其他人合作学习 中心和国际移植登记中心已经成立。 为了这个目的。第三个目标将是通过体外方法确认 多肽特异性的CD4+T辅助细胞之间的认知相互作用 通过同种异体识别B提出的人类白细胞抗原I类多肽而发生 淋巴细胞。 这些发现在脑血管疾病领域的潜在临床意义 器官移植的规模相当大。第一，理解 是什么决定了人类白细胞抗原的免疫原性和控制因素 调节抗体反应的规则最终可能被应用于 确定有可能产生人类白细胞抗原抗体的移植候选者 针对一种特定的异体移植物(“应答者表型”)。第二, 作为补充，分子匹配的新策略可能是 适用于有先天证据的患者 应答者表型。第三，减少或消除幽默 使用这些策略的效应器电路，定制可能是可行的 个人的免疫抑制药物，基于类型和 人类白细胞抗原不匹配程度和/或制定诱导策略 T细胞对供者同种异体移植物的无能或耐受性。最重要的是， 避免体液致敏可降低移植成功率 与移植相关的排斥反应和相应的经济消耗 失败以及随之而来的慢性医疗护理费用。

The objectives of this proposal are to define the molecular and the cellular mechanisms that control a person's ability to produce an HLA antibody response against the Class I histocompatibility antigens. Our ultimate goal will be to provide a scientific basis for beginning to devise innovative strategies to minimize or eliminate the induction of a humoral HLA response. These investigations hinge on the hypothesis that immune regulation is dictated primarily through the classical mechanism of immune response (Ir) genes, controlled primarily by the ability of the host's HLA Class II antigens to bind and present foreign HLA allopeptide to CD4+ T lymphocytes (helper cells). HLA alloantibody formation is then initiated through cooperative interactions between these activated T lymphocytes in concert with B lymphocytes that possess the appropriate immunoglobulin receptors and Ir gene products. There are three specific aims to this proposal. The first is to map the patterns of HLA Class II antigen restriction using a library of synthetic HLA Class I peptides representing polymorphic domains of two major families of HLA antigens, HLA-A2 and HLA-B7. Direct peptide binding assays with viable cells will be performed using analytical flow cytometry. The second aim will be to determine whether these Ir genes correlate in vivo with the capacity to produce specific HLA alloantibody and whether these factors contribute to chronic vasculopathy of the allograft and ultimately, graft failure. Collaborative studies with other centers and with an international transplant registry have been organized for this purpose. The third aim will be to confirm by in vitro methods that cognitive interactions between peptide-specific CD4+ T helper cells occur through allorecognition of HLA Class I peptides presented by B lymphocytes. The potential clinical significance of these findings in the field of organ transplantation is of considerable magnitude. First, understanding what dictates both HLA immunogenicity and the controlling factors or rules that regulate antibody responses could eventually be applied to identify transplant candidates who are at risk to produce HLA antibody against a particular foreign allograft ("responder phenotype"). Second, complementary to this, new strategies for molecular matching could be applied for patients who are identified a priori as possessing the responder phenotype. Third, with reduction or elimination of the humoral effector circuit using these strategies, it may be feasible to customize an individual's immunosuppressive medications based on the type and the degree of HLA antigen mismatch and/or to devise strategies for induction of T cell anergy or tolerance to the donor allograft. Most important, avoidance of humoral sensitization could reduce the rate of transplant rejection and the corresponding economic drain associated with graft failure and the ensuing costs accompanying chronic medical care.