MEMORY AND REGULATORY T CELLS FOLLOWING T CELL DEPLETION IN TRANSPLANTATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们已经使用了一种淋巴细胞耗竭模型在恒河猴给予一种新的抗CD 3免疫毒素融合蛋白（IT）的受体猴在同种异体肾移植的时间。 单用IT治疗的猴在3周内产生抗供体肾的抗体，血清Cr升高，并有抗体介导的排斥反应的活检证据。 我们已经定义了淋巴细胞再增殖动力学，同种抗体的产生，抗体介导的排斥反应，在这个模型中，并使用这些数据来衡量治疗方案的影响，旨在防止抗体介导的排斥反应，除了控制急性排斥反应的T细胞介导的。 用抗CD 3免疫毒素去除淋巴细胞促进中央记忆T细胞的稳态增殖，其随后是包括同种抗体产生的全身性同种免疫应答。 在T细胞耗竭后，用他克莫司和阿法赛特充分控制急性细胞排斥事件允许单独监测同种抗体产生和抗体介导的排斥事件。 实施该模型用于B细胞治疗的应用可以进一步阐明供体特异性抗体介导进行性同种异体移植物功能障碍和慢性排斥的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have used a lymphocyte depleting model in rhesus macaques by administering a novel anti-CD3 immunotoxin fusion protein (IT) to recipient monkeys at the time of allogeneic renal transplantation. Monkeys treated with IT alone develop antibody to donor kidney within 3 weeks, rising serum Cr, and biopsy evidence of antibody-mediated rejection. We have defined the lymphocyte repopulation kinetics, alloantibody production, and antibody-mediated rejection in this model and used these data to measure the impact of treatment regimens aimed at preventing antibody-mediated rejection in addition to controlling acute rejection mediated by T cells. Lymphocyte depletion with anti-CD3 immunotoxin promotes homeostatic proliferation of central memory T cells, which is succeeded by a generalized alloimmune response including alloantibody production. Adequate control of acute cellular rejection episodes with tacrolimus and alefacept after T cell depletion allows for isolated monitoring of alloantibody production and antibody-mediated rejection events. Implementing this model for the application of B cell therapeutics may further elucidate mechanisms through which donor-specific antibodies mediate progressive allograft dysfunction and chronic rejection.