MEMORY AND REGULATORY T CELLS FOLLOWING T CELL DEPLETION IN TRANSPLANTATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们在恒河猴中使用了一种淋巴细胞耗尽模型，在异基因肾移植时给受体猴注射了一种新型的抗CD3免疫毒素融合蛋白(IT)。单独接受IT治疗的猴子在3周内产生对供体肾脏的抗体，血清肌酐升高，并有抗体介导的排斥反应的活组织检查证据。我们在这个模型中定义了淋巴细胞再繁殖动力学、同种异体抗体产生和抗体介导的排斥反应，并使用这些数据来衡量除了控制T细胞介导的急性排斥反应外，还旨在防止抗体介导的排斥反应的治疗方案的影响。 用抗CD3免疫毒素耗尽淋巴细胞可促进中央记忆T细胞的动态平衡增殖，随后是包括产生同种抗体在内的全身同种异体免疫反应。在T细胞耗尽后，使用他克莫司和阿法塞特充分控制急性细胞排斥反应，可以单独监测同种异体抗体的产生和抗体介导的排斥事件。将这一模型应用于B细胞疗法可能会进一步阐明供者特异性抗体介导进行性同种异体移植功能障碍和慢性排斥反应的机制。

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.