GENETIC CONTROL OF HLA CLASS I ALLOANTIBODY RESPONSES

本提案的目标是定义分子和 控制一个人产生HLA的能力的细胞机制 针对I类组织相容性抗原的抗体应答。我们 最终目标将是为开始提供科学依据， 制定创新战略，尽量减少或消除 体液HLA反应这些调查都基于这样一种假设， 免疫调节主要通过经典机制来决定 免疫反应（Ir）基因，主要由免疫系统的能力控制。 宿主HLA II类抗原结合并呈递外源HLA同种异体肽 CD4 + T淋巴细胞（辅助细胞）。HLA同种抗体的形成， 通过这些激活的T细胞之间的合作相互作用启动 淋巴细胞与B淋巴细胞一致，具有适当的 免疫球蛋白受体和Ir基因产物。 这项建议有三个具体目标。第一个是映射 使用人工合成的HLA-II类抗原限制性抗体库， HLA I类肽代表两个主要的 HLA抗原家族，HLA-A2和HLA-B7。直接肽结合 将使用分析流程进行活细胞测定 细胞仪第二个目标是确定这些Ir基因是否 体内与产生特异性HLA同种抗体的能力相关 以及这些因素是否会导致 同种异体移植最终导致移植失败与其他机构的合作研究 中心和国际移植登记处已经组织起来 为此目的。第三个目标是通过体外方法确认 肽特异性CD4 + T辅助细胞之间的认知相互作用 通过B呈递的HLA I类肽的同种异体识别发生 淋巴细胞 这些发现在以下领域的潜在临床意义： 器官移植的规模相当大。第一，理解 什么决定了HLA免疫原性和控制因素， 调节抗体反应的规则最终可以应用于 识别有产生HLA抗体风险移植候选人 针对特定的外源同种异体移植物（"应答表型"）。第二、 与此互补的是，新的分子匹配策略可能是 适用于先验确定为具有 应答者表型第三，随着体液免疫功能的减少或消除， 效应器电路使用这些策略，它可能是可行的定制 根据类型和患者的免疫抑制药物， HLA抗原错配的程度和/或设计诱导策略 T细胞对同种异体移植物无反应或耐受。最重要的是， 避免体液致敏可降低移植率 排斥反应和与移植相关的相应经济损失 失败和随之而来的费用伴随着慢性医疗护理。

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.