T Cell Maturation and the Nexus of Viral- and Allo-Immunity

描述（申请人提供）：器官移植的显著益处被与其所需的慢性免疫抑制治疗相关的并发症显著抵消。患者通常服用几种药物，但钙调磷酸酶抑制剂（CNIs）长期以来一直是大多数治疗方案的核心。CNI有效地防止排斥，但它们的使用与非抗原特异性T细胞抑制、随后的保护性免疫受损和许多非免疫副作用相关。今年，一种CNI替代品已被批准：贝拉西普，一种介导CD 28-B7共刺激阻断（CoB）的融合蛋白。大量临床证据表明，贝拉西普可以作为CNI替代品，避免CNI特异性脱靶副作用。然而，贝拉西普在某些情况下似乎不太能够防止排斥，并且不均匀地损害病毒免疫，特别是针对常见的Epstein -巴尔病毒。因此，临床医生现在有两种不同的方法来预防移植排斥反应，CNI和CoB为基础的免疫抑制，但很少有数据指导他们之间的合理选择。本申请接近移植中的这一高度当代的困境，CNI/贝拉西普的选择及其与排斥和病毒感染的相互并发症的关系。我们假设排斥反应和病毒感染是机械相关的，通过一个过程称为异源同种异体免疫-同种异体免疫成熟的前病毒感染-和已知的T细胞表型的变化出现在整个生命和影响同种异体和病毒免疫可以用来预测一个人的反应CNIs和CoB。我们相信，这些表型变化可用于开发一种生物学上合理的、治疗相关的和诊断上可定义的方法，将受益于基于贝拉西普的方案的患者与更好地受益于基于CNI的方法的患者分开。我们在三个特定目的中探索了这一假设，一项在人类中进行的观察性研究，以确定在CNI或贝拉西普治疗的背景下，病毒感染和排斥与肾移植受者T细胞分化和耗竭的程度，以及两个使用定义明确的，临床相关的，移植和病毒感染的小鼠模型，以建立确定CNI和CoB对同种异体和病毒特异性免疫的特异性作用的机制。为这项研究组建的调查小组很容易使用移植患者的观察结果来指导严格控制的动物研究，并使用新的动物实验来修改人体研究。它集中在一个高容量移植中心，该中心已经开发了一个优秀的基础设施，用于采集特征良好的人体样本，并对接受CNI和贝拉西普方案的患者进行特殊暴露。因此，每个目标都将在认识到相关临床情况和机械原理的情况下进行。这项研究将有助于发展一个统一的范式，以指导免疫抑制剂的合理选择，并促进移植患者的个体化，数据驱动，免疫管理。

DESCRIPTION (provided by applicant): Organ transplantation's considerable benefit is significantly offset by the complications associated with its required chronic immunosuppressive therapy. Patients are usually on several medications, but calcineurin inhibitors (CNIs) have long formed the centerpiece of most regimens. CNIs effectively prevent rejection, but their use is associated with non-antigen-specific T cell suppression, consequent impaired protective immunity, and numerous non-immune side effects. This year, a CNI alternative has been approved: belatacept, a fusion protein that mediates CD28-B7 costimulation blockade (CoB). Substantial clinical evidence suggests that belatacept can serve as a CNI replacement, avoiding CNI-specific off-target side effects. However, belatacept appears less able to prevent rejection in certain scenarios, and to inhomogenously impair viral immunity, particularly towards the common Epstein - Barr virus. Thus, clinicians now have two distinct approaches to prevent transplant rejection, CNI- and CoB-based immunosuppression, but little data guiding a rational choice between them. This application approaches this highly contemporary dilemma in transplantation, the CNI/belatacept choice and its relationship to the reciprocal complications of rejection and viral infection. We hypothesize that rejection and viral infection are mechanisticall related through a process known as heterologous alloimmunity-alloimmunity matured by prior viral infection-and that the changes in T cell phenotype known to emerge throughout life and influence allo- and viral-immunity can be used to anticipate one's response to CNIs and CoB. We believe these phenotypic changes can be used to develop a biologically plausible, therapeutically relevant, and diagnostically definable means of segregating those patients who will benefit from a belatacept-based regimen from those better served by a CNI-based approach. We explore this hypothesis in three Specific Aims, one observational study in humans to define the extent to which viral infection and rejection relate to kidney transplant recipients' T cell differentiation and exhaustion in the context of CNI- or belatacept-based therapy, and two experimental projects performed using well-defined, clinically relevant, mouse models of transplantation and viral infection to establish the mechanisms determining CNI- and CoB-specific effects on allo- and viral-specific-immunity. The investigative team formed for this study is facile in using observations in transplant patients to inform the conduct of rigorously controlled animal studies, and in the use of novel animal experiments to modify human studies. It is centered in a high volume transplant center that has developed an outstanding infrastructure for the acquisition of well-characterized human samples, and exceptional exposure to patients undergoing CNI- and belatacept-based regimens. Thus, each aim will be conducted cognizant of both the relevant clinical circumstances and mechanistic principles. This study will facilitate development of a unifying paradigm to guide the rational selection of immunosuppressive agents, and facilitate individualized, data-driven, immunological management for transplant patients.