THYMUS TRANSPLANTATION

胸腺移植

• 批准号: 6630541
• 负责人: DAVID H SACHS
• 金额: $ 25.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630541
• 关键词: AIDS therapy; HIV infections; T lymphocyte; baboons; cell transplantation; hematopoietic stem cells; humoral immunity; immune tolerance /unresponsiveness; immunotherapy; leukopoiesis; miniature swine; nonhuman therapy evaluation; stem cell transplantation; thymus transplantation; transplantation immunology; xenotransplantation

DESCRIPTION: (Provided by applicant): The ultimate goal of the studies in this Program Project is the restoration of thymic function in AIDS patients by replacement of HIV-infected thymic stroma with healthy porcine tissue through thymic xenotransplantation. Previous studies in a murine model demonstrated the capacity of porcine fetal thymus transplants to reconstitute normal T cell populations in thymectomized, T cell-depleted animals. The current project is directed toward extending these findings to non-human primates as a preclinical model. As donors, we are utilizing inbred miniature swine, which have been developed in this laboratory as a large animal model in which MHC genetics can be reproducibly controlled, and which are of appropriate size and availability to serve as xenograft donors for eventual clinical use. In the previous funding period, we have established conditions for successful engraftment of juvenile pig thymus into peripheral sites in autologous and allogeneic miniature swine. We have found the combination of omentum plus either muscle or renal capsule to be most effective sites for implantation of thymic tissue in these large animals. We have also initiated studies of porcine thymic transplantation into baboons. Our preliminary data demonstrate successful engraftment of pig thymic tissue in thymectomized, T cell-depleted baboons for up to 60 days by histologic criteria. We have demonstrated recovery of CD4SP/CD45RA high cells in thymic grafted animals, but not in controls not receiving thymus, and specific depression of the baboon anti-pig MLR for several months after transplantation. We have also demonstrated the feasibility of transplanting vascularized pig thymus as part of a composite organ. Our specific aims for the current proposal are to: 1) Achieve successful long-term engraftment of porcine thymus transplants in non-human primates; 2) Evaluate immune reconstitution of thymectomized, T cell depleted recipients following porcine thymic transplantation; and 3) Combine thymic transplantation with peripheral stem cell transplantation for induction of tolerance. The results of these studies could have important implications for the application of this treatment modality to patients suffering from AIDS.

描述：（由申请人提供）：本研究的最终目标 计划项目是通过以下方法恢复艾滋病患者的胸腺功能 用健康猪组织替代感染艾滋病毒的胸腺基质 胸腺异种移植。先前的小鼠模型研究表明 猪胎儿胸腺移植重建正常 T 细胞的能力 胸腺切除、T 细胞耗尽的动物群体。目前的项目是 旨在将这些发现扩展到非人类灵长类动物 临床前模型。作为捐助者，我们正在利用近交小型猪， 该实验室已开发出 MHC 大型动物模型 遗传可以重复控制，并且具有适当的大小和 可作为最终临床使用的异种移植供体。在 在之前的资助期间，我们已经为成功创造了条件 将幼猪胸腺植入自体和外周部位 同种异体小型猪。我们找到了网膜加的组合 肌肉或肾被膜是最有效的植入部位 这些大型动物的胸腺组织。我们还启动了研究 将猪胸腺移植到狒狒体内。我们的初步数据表明 猪胸腺组织在胸腺切除、T细胞耗尽的情况下成功植入 根据组织学标准，狒狒可存活长达 60 天。我们已经证明了 胸腺移植动物中 CD4SP/CD45RA 高细胞的恢复，但在 对照不接受胸腺，狒狒抗猪的特异性抑制 移植后几个月MLR。我们还展示了 移植带血管的猪胸腺作为复合材料的一部分的可行性 器官。我们当前提案的具体目标是： 1) 实现 猪胸腺移植物在非人类体内成功长期植入 灵长类动物； 2) 评估胸腺切除、T 细胞耗尽的免疫重建 猪胸腺移植后的受者； 3) 结合胸腺 外周干细胞移植诱导 宽容。这些研究的结果可能具有重要意义 将这种治疗方式应用于艾滋病患者。