RESTORATION OF TCR REPERTOIRE AFTER DEPLETION

T细胞在引发移植组织的免疫排斥反应中起重要作用。 已经做出了重大努力来探索诱导供体特异性免疫耐受以实现长期移植物存活而不需要终身免疫抑制治疗的潜力。 非人灵长类动物是检测同种异体移植免疫耐受的理想动物模型。 最近在Judy托马斯博士的实验室进行的工作表明，用抗CD 3免疫毒素（IT）治疗恒河猴导致了严重的T细胞耗竭，并诱导了长达3年的稳定耐受性，而没有慢性同种异体移植排斥反应。 虽然IT协议显然有利于诱导猕猴同种异体移植物的耐受性，重要的问题仍然有待探讨的基础T细胞免疫学和未来应用的IT策略，尸体移植耐受诱导人类。基于该结果，证明了T细胞耗竭的猕猴中的猕猴谱系的能力可以通过胸腺依赖性和/或非依赖性途径不同程度地恢复。 我们还假设同种异体抗原可能驱动与同种异体移植排斥或耐受相关的显性T细胞反应。 为了验证这些假设，我们将：确定T细胞耗竭后猕猴TCR库的恢复。 A.确定幼年猕猴T细胞耗竭后TCR库的恢复。 B。确定T细胞耗竭后老年猕猴中TCR库的恢复。二. 评估T细胞耗竭后年轻和老年猕猴中基于TCR的胸腺输出。 三. 猕猴肾移植排斥反应TCR谱的测定。

T cells play an important role in triggering the immune rejection of transplanted tissues. Significant efforts have been made to explore the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for life-long immunosuppressive therapy. Non-human primates are ideal animal models to test the immune-target tolerance for successful allotransplantation. Recent work done in Dr. Judy Thomas' laboratory has shown that the treatment of rhesus monkeys with anti-CD3-Immunotoxin (IT) resulted in profound T cell depletion, and induced stable tolerance without chronic allograft rejection for up to 3 years. While IT protocol clearly facilitates inducing the tolerance of allografts in macaques, important questions remain to be explored regarding fundamental T cell immunology and future application of the IT strategy to cadaveric transplant tolerance induction in humans. Based on the result demonstrating the ability of macaque repertoires in the macaques depleted of T cells can be restored to various degrees through the thymic-dependent and/or-independent pathways. We also hypothesize that alloantigens may drive the dominant T cell response that is relevant to allograft rejection or tolerance. To test these hypothesis, we will: I. Determine restoration of macaque TCR repertoires following T cell depletion. A. Determine restoration of TCR repertoires in juvenile macaques following T cell depletion. B. Determine restoration of TCR repertoires in old macaques following T cell depletion. II. Assess TCR-based thymic output in young and old macaques after T cell depletion. III. Determine the TCR repertoire in rejected kidney allografts of macaque recipients.