INDUCTION OF ALLOGRAFT TOLERANCE

这项建议旨在研究供者特异性的机制。 混合异基因骨髓嵌合体诱导同种异体移植耐受 在临床相关的猴子模型中。这样做的具体目的是 该项目包括确定来自供体骨骼的特定细胞 骨髓是建立免疫耐受所必需的，以及 不需要长期的嵌合体来保持对 异体移植。在供体来源细胞无法检测到的耐受性动物中 在外周血液中，淋巴组织将被广泛检查 嵌合体的证据。同种异体移植物本身在移植中的作用 长期免疫耐受的维持也将被研究。 捐赠者的骨髓将使用磁珠分离 用mAbs标记的细胞与特定的细胞谱系标记。这个 特定的骨髓细胞亚群将被转移到MHC 不匹配的受体已经遭受了非致命性 允许骨髓植入和建立的准备方案 混杂的嵌合体。然后对淋巴组织进行检查 免疫组织化学和聚合酶链式反应检测供者来源的细胞系 骨髓移植后的连续时间。受辐射的骨髓会 在肾移植时被转移，以确定是否 捐献的骨髓被动地充当抗原的来源，而不是 积极参与建立宽容的关系。这些研究将有 对理解灵长类动物耐受性的重要意义 可能最终导致建立临床方案来预防 跨越同种异体障碍的器官移植排斥反应 慢性免疫抑制。

This proposal is designed to study the mechanism of donor specific allograft tolerance induced through mixed allogeneic bone marrow chimerism in the clinically relevant monkey model. The specific aims of this project include determining what particular cells from the donor bone marrow are necessary to establish immunological tolerance and whether or not long-term chimerism is necessary to maintain tolerance to the allograft. In tolerant animals whose donor derived cells are undetectable in the peripheral blood, lymphoid tissues will be extensively examined for evidence of chimerism. The role of the allograft itself in the maintenance of long-term immunological tolerance will also be studied. Donor bone marrow will be fractionated using magnetic bead separation of cells labeled with mAbs to particular cell lineage markers. The particular bone marrow cell subsets will be transferred into MHC mismatched recipients which have been subjected to the non-lethal preparative regimen to allow for bone marrow engraftment and establishment of mixed chimerism. Lymphoid tissues will then be examined by immunohistochemistry and by PCR to detect donor derived cell lineages at sequential times after bone marrow transfer. Irradiated bone marrow will be transferred at the time of kidney transplant to determine whether the donor bone marrow acts passively as a source of antigen rather than actively in the establishment of tolerance. These studies will have important implications for the understanding of tolerance in primates and may ultimately lead to establishment of clinical protocols to prevent organ transplant rejection across allogeneic barriers without the need for chronic immunosuppression.