RESTORATION OF TCR REPERTOIRE AFTER DEPLETION

TCR 耗尽后的恢复

• 批准号: 6655229
• 负责人: Zheng W Chen
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655229
• 关键词: Macaca mulatta; T cell receptor; T lymphocyte; age difference; animal old age; cell population study; cooperative study; flow cytometry; gene expression; histocompatibility; homologous transplantation; immune tolerance /unresponsiveness; immunoconjugates; immunogenetics; immunosuppressive; juvenile animal; kidney transplantation; lymphocyte proliferation; monoclonal antibody; thymus; transplant rejection; transplantation immunology

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.

T细胞在触发移植组织的免疫排斥反应中起重要作用。 已经做出了巨大的努力，以探索诱导供体特异性免疫耐受性以实现长期移植物生存的潜力，而无需终身免疫抑制疗法。 非人类灵长类动物是成功测试成功同倍移植的免疫目标耐受性的理想动物模型。 在朱迪·托马斯（Judy Thomas）博士的实验室中所做的最新工作表明，用抗CD3-免疫毒素（IT）对恒河猴的治疗导致T细胞耗尽，并诱导稳定的耐受性，而无需慢性同种异体移植排斥，最多3年。 尽管IT方案清楚地促进了猕猴中同种异体移植的耐受性，但有关基本T细胞免疫学和IT策略对人类诱使诱导人类诱导的IT策略的未来应用仍有待探讨的重要问题。基于结果表明，可以通过乳腺依赖性和/或独立的途径将猕猴猕猴枯萎的能力恢复到各种程度。 我们还假设同种抗原可能会驱动与同种异体移植排斥或耐受性相关的主要T细胞反应。 为了检验这些假设，我们将：I。确定T细胞耗竭后猕猴TCR曲目的恢复。 答：确定T细胞耗竭后，幼年猕猴中TCR曲目的恢复。 B.确定T细胞耗竭后旧猕猴中TCR曲目的恢复。 ii。 评估T细胞耗竭后的年轻和老猕猴中基于TCR的胸腺输出。 iii。 确定滞后猕猴的肾脏同种异体移植物中的TCR曲目。