RESTORATION OF TCR REPERTOIRE AFTER DEPLETION

T细胞在触发移植组织的免疫排斥反应中起着重要作用。人们已经做出了重大努力来探索诱导供者特异性免疫耐受的可能性，以实现移植物的长期存活，而不需要终身免疫抑制治疗。非人灵长类动物是检测同种异体移植成功的免疫靶标耐受性的理想动物模型。最近在朱迪·托马斯博士的实验室所做的工作表明，用抗CD3免疫毒素(IT)治疗恒河猴可导致严重的T细胞耗竭，并诱导稳定的耐受，长达3年的同种异体移植无慢性排斥反应。虽然IT方案明显促进了猕猴同种异体移植耐受的诱导，但关于基础T细胞免疫学和未来IT策略在人类身体移植耐受诱导中的应用，仍有重要的问题有待探索。根据这一结果，短尾猴体内T细胞耗竭的能力可以通过胸腺依赖和/或非胸腺依赖的途径得到不同程度的恢复。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：1.确定T细胞耗尽后猕猴TCR谱系的恢复。A.确定幼年猕猴在T细胞耗尽后TCR谱系的恢复。B.确定T细胞耗尽后老年猕猴TCR谱系的恢复。II.评估年轻和老年猕猴在T细胞耗尽后基于TCR的胸腺输出。III.确定猕猴排斥移植肾的TCR谱系。

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.