Immune Tolerance in Mixed Chimeric Miniature Swine

描述(申请人提供)：器官移植已成为 广泛治疗许多终末期肾、肝、心、肾、肾、心、肾、心、肾、肝、心、肾、肾、肝、心、肾、肝、心、 和肺部疾病。然而，两大障碍阻碍了更大的 成功的是供体器官的可获得性和治疗相关的并发症 包括急性和慢性移植物排斥反应。避免被拒绝的一种尝试是 通过创造特定的移植耐受，定义为消除 受体的？S对移植器官的免疫反应？S的异源抗原 同时保持其他主机响应不变。宽容代表着 现代移植生物学，也是本研究提案的重点。 具体地说，萨克斯实验室已经开发出一种大型动物模型 使用已知MHC单倍型的近交系小型猪的耐受性。使用 非骨髓抑制制剂和大剂量外周血干细胞 移植方案混合淋巴造血嵌合体和移植 可以在这些动物身上诱导耐受性。当混合嵌合体猪经历 来自同一干细胞供者的后续肾移植 移植他们接受没有外源性免疫抑制的肾移植。 这一建议将描述免疫耐受的细胞性。 在这些动物身上产生。将特别关注对观察到的 捐献者来源的T细胞的持久亚群，以努力确定 它们的起源、身份和功能活动。研究设计包括 干细胞移植前对供者接种的标记以确定 持续性T细胞群体的遗传性以及CML和MLR分析 评估这些细胞对受体的体外反应性。重要的是 将通过将他们转移到匹配的 幼稚的动物来决定它们是否能在这个新的宿主和 也许会让那只动物产生耐受性。对手机和手机的理解 在分子水平上，这种持久捐赠者T细胞群体的性质是 对理解移植耐受性的本质至关重要 这些非凡的动物。

DESCRIPTION (provided by the applicant): Organ transplantation has become a widespread treatment for many patients with end-stage renal, hepatic, cardiac, and pulmonary disease. However, two major obstacles preventing greater successes are donor organ availability and treatment related complications including acute and chronic graft rejection. One attempt to avoid rejection is via the creation of specific transplantation tolerance, defined as elimination of the recipient?s immune response to a transplanted organ?s foreign antigens while leaving other host responses intact. Tolerance represents a major goal of modern transplant biology and is the focus of this research proposal. Specifically, the Sachs laboratory has developed a large animal model of tolerance using inbred miniature swine of known MHC haplotype. Using a non-myelosuppressive preparation and a high dose peripheral blood stem cell transplant protocol mixed lymphohematopoietic chimerism and transplant tolerance can be induced in these animals. When mixed chimeric swine undergo subsequent renal transplantation from the same donor of their stem cell transplant they accept a kidney graft with no exogenous -immunosuppression. This proposal will characterize the cellular nature of the immune tolerance generated in these animals. Special focus will be on study of an observed persistent sub-population of T-cells of donor origin in an effort to determine their origin, identity, and functional activity. Research design includes labeling of the donor inoculum prior to stem cell transplant to determine the heredity of the persistent T-cell population as well as CML and MLR assays to assess in vitro reactivity of these cells to the recipient. The importance of this population will be further assessed by transferring them to a matched naive animal to determine whether they will survive in this new host and perhaps create tolerance in that animal. Understanding on a cellular and molecular level the nature of this persistent donor T-cell population is crucial to understanding the nature of the transplant tolerance created in these remarkable animals.