Effects of Rapamycin and Donor-Specific Transfusions on Activation-Induced Cell Death (AICD) and the Induction of Tolerance to Cardiac Allografts in Miniature Swine

目前对同种异体移植物排斥的治疗需要全身性的慢性免疫抑制，这与使人衰弱的药物特异性副作用、感染、癌症和慢性排斥有关。克服所有这些问题的最佳方法是在宿主中诱导对供体同种异体抗原的特异性耐受。这将允许长期接受移植器官而不需要免疫抑制，同时保持宿主抵抗感染和恶性肿瘤的能力。已经确定，特异性识别移植的同种异体抗原的T细胞是急性排斥反应的原因，并且它们也有助于慢性同种异体移植物排斥反应。来自先前动物研究的数据表明，多种T细胞相关机制参与了耐受性的诱导。根据最近的啮齿动物数据，通过活化诱导细胞死亡（AICD）删除大的同种异体反应性T细胞库是稳定耐受所必需的。然而，这一发现尚未在大型动物系统中确立。本研究的目的是测试这一假设，即促进AICD将允许诱导耐受的主要组织相容性复合体（MHC）近交系小型猪心脏同种异体移植。我们将使用高剂量供体特异性输血结合短期雷帕霉素诱导同种异体反应性T细胞池的AICD。通过这种策略诱导快速和稳定的耐受将具有重要的临床意义。

Current treatment for allograft rejection requires generalized, chronic immunosuppression, which is associated with debilitating drug-specific side effects, infection, cancer and chronic rejection. The optimal way to overcome all these problems is to induce specific tolerance to donor alloantigens in the host. This would allow long-term acceptance of transplanted organs without immunosuppression, and at the same time preserve the host's ability to fight infection and malignancy. It has been established that T cells that specifically recognize the transplanted alloantigen are responsible for acute rejection and that they also contribute to chronic allograft rejection. Data emerging from prior animal studies indicate that multiple T cell-related mechanisms are involved in the induction of tolerance. According to recent rodent data, deletion of the large alloreactive T cell pool by activation induced cell death (AICD) is necessary for stable tolerance. However, this finding has not been established in a large animal system. The aim of this study is test the hypothesis that facilitating AICD will permit the induction of tolerance to a cardiac allograft in major histocompatibility complex (MHC) inbred miniature swine. We will use high dose donor specific transfusions combined with a short course of rapamycin to induce AICD of the alloreactive T cell pool. The induction of rapid and stable tolerance via this strategy would have important clinical implications.