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

描述（由申请人提供）：器官移植的巨大益处被其所需的慢性免疫抑制治疗相关的并发症显著抵消。患者通常需要服用几种药物，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。CNIs可有效预防排斥反应，但其使用与非抗原特异性T细胞抑制、随之而来的保护性免疫受损以及许多非免疫副作用有关。今年，一种CNI替代品被批准：belatacept，一种介导CD28-B7共刺激阻断（CoB）的融合蛋白。大量临床证据表明，belatacept可作为CNI替代品，避免CNI特异性脱靶副作用。然而，在某些情况下，belataccept似乎不能防止排斥反应，并且不均匀地损害病毒免疫，特别是对常见的Epstein - Barr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和基于cob的免疫抑制，但很少有数据指导他们之间的理性选择。这种应用接近了移植中高度现代的困境，即CNI/ belataccept的选择及其与排斥反应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通过一种被称为异源异体免疫（同种异体免疫由先前的病毒感染成熟）的过程在机制上都是相关的，并且已知在生命中出现的T细胞表型的变化和影响异体和病毒免疫的变化可以用来预测一个人对CNIs和CoB的反应。我们相信这些表型变化可以用来开发一种生物学上合理的、治疗上相关的、诊断上可定义的方法，以区分那些将受益于基于belataccept的方案的患者和那些更好地服务于基于cni的方法的患者。我们在三个特定目标中探索了这一假设，一个是在人类中进行的观察性研究，以确定病毒感染和排斥与肾移植受者在CNI或belataccept为基础的治疗背景下的T细胞分化和衰竭的关系程度，以及两个实验项目，使用定义良好的，临床相关的，建立小鼠移植和病毒感染模型，以确定CNI和cob特异性对同种异体和病毒特异性免疫的影响机制。为这项研究组建的调查小组很容易利用对移植患者的观察来指导严格控制的动物研究，并利用新的动物实验来修改人类研究。它集中在一个大容量移植中心，该中心已经开发了一个出色的基础设施，用于获取具有良好特征的人类样本，以及接受CNI和belataccept为基础的方案的患者的特殊暴露。因此，每个目标都将在认识到相关临床情况和机制原则的情况下进行。本研究将促进统一范式的发展，以指导免疫抑制剂的合理选择，并促进移植患者个性化的、数据驱动的免疫管理。

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.