INDUCTION OF ALLOGRAFT TOLERANCE

本文旨在研究捐赠者特定的机制， 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。 具体目标是 该项目包括确定哪些特定的细胞从供体骨 骨髓是建立免疫耐受所必需的， 而不是长期嵌合体是必要的，以维持耐受性， 同种异体移植 在无法检测到供体来源细胞的耐受动物中 在外周血中，将广泛检查淋巴组织， 嵌合体的证据 同种异体移植物本身在 还将研究长期免疫耐受性的维持。 供体骨髓将使用磁珠分离进行分级， 用mAb标记的细胞与特定细胞谱系标记物的结合。 的 特定的骨髓细胞亚群将被转移到MHC中， 不匹配的接受者已经受到了非致命的 允许骨髓移植和建立的准备方案 混合嵌合体 然后将通过以下方法检查乳突组织： 免疫组织化学和PCR检测供体来源的细胞系， 在骨髓移植后的连续时间。 辐射骨髓将 在肾移植时转移，以确定是否 供体骨髓被动地充当抗原来源，而不是 积极倡导宽容。 这些研究将 对理解灵长类动物的耐受性具有重要意义， 可能最终导致建立临床协议，以防止 器官移植排斥反应跨越同种异体屏障，而不需要 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.