Immune Tolerance in Mixed Chimeric Miniature Swine

描述（由申请人提供）：器官移植已成为 广泛治疗许多终末期肾，肝，心， 和肺部疾病。然而，两个主要障碍阻止了更大的 成功是供体器官的可用性和治疗相关的并发症 包括急性和慢性移植排斥。避免拒绝的一种尝试是 通过产生特异性移植耐受，定义为消除 接受者的？对移植器官的免疫反应？s外源抗原 而不影响其他宿主的反应。宽容是一个主要的目标， 现代移植生物学，是这项研究计划的重点。 具体来说，萨克斯实验室已经开发了一种大型动物模型， 使用已知MHC单倍型的近交小型猪的耐受性。使用 非骨髓抑制制剂和高剂量外周血干细胞 混合淋巴造血嵌合体和移植方案 可以在这些动物中诱导耐受性。当混合嵌合体猪经历 来自同一个干细胞供体的后续肾移植 他们接受没有外源性免疫抑制的肾脏移植。 该建议将表征免疫耐受的细胞性质 在这些动物身上产生的。特别重点将是研究一个观察到的 供体来源的T细胞的持续亚群，以确定 它们的起源、身份和功能活动。研究设计包括 在干细胞移植之前标记供体接种物以确定 持久性T细胞群的遗传以及CML和MLR测定， 评估这些细胞对受体的体外反应性。的重要性 将通过将其转移到匹配的 幼稚的动物，以确定他们是否会生存在这个新的主机， 也许能让动物产生耐受性了解细胞和 在分子水平上，这种持久的供体T细胞群体的性质是 这对于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.