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与其所需的慢性免疫抑制治疗相关的并发症所显著抵消。患者通常服用几种药物，但钙调神经磷酸酶抑制剂(CNI)长期以来一直是大多数方案的核心。CNI可以有效地防止排斥反应，但它们的使用会导致非抗原特异性T细胞抑制，继而导致保护性免疫受损，以及许多非免疫性副作用。今年，CNI的替代品已经获得批准：belatacept，一种介导CD28-B7共刺激阻断(COB)的融合蛋白。大量的临床证据表明，贝拉塔塞特可以作为CNI的替代品，避免CNI特异性的非靶向副作用。然而，在某些情况下，belatacept似乎不能防止排斥反应，并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截然不同的方法来预防移植排斥反应，即基于CNI和CoB的免疫抑制，但几乎没有数据指导两者之间的合理选择。这一应用解决了移植中的高度当代困境，CNI/belatacept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都是通过一个称为异种同种免疫的过程机制相关的--同种免疫是由先前的病毒感染成熟的--并且已知在一生中出现并影响同种和病毒免疫的T细胞表型的变化可以用于预测一个人对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可行的、与治疗相关的、在诊断上可定义的方法，将那些将从基于拉他赛普的方案中受益的患者与那些更好地从基于CNI的方法中受益的患者分开。我们从三个具体目标来探讨这一假说，一项是在人类中进行的一项观察性研究，目的是在基于CNI或贝拉塔塞特的治疗背景下，确定病毒感染和排斥反应与肾移植受者T细胞分化和衰竭的程度，以及两项实验项目，该项目使用定义明确的、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对同种和病毒特异性免疫的特定影响的机制。为这项研究组成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的进行，并使用新的动物实验来修改人类研究。它集中在一个大容量的移植中心，该中心已经为获取具有良好特征的人体样本开发了出色的基础设施，并特别暴露于接受CNI和贝拉西普为基础的治疗方案的患者。因此，每个目标的实现都要考虑到相关的临床情况和机械原理。这项研究将有助于建立一个统一的范式来指导免疫抑制剂的合理选择，并促进移植患者的个性化、数据驱动的免疫管理。 公共卫生相关性：拟议的研究与公共健康相关，因为它旨在进行机械驱动的研究，以总体上优化免疫抑制的实施，特别是belatacept(共刺激阻断)，作为预防器官移植后排斥反应的替代策略。选择适当的免疫抑制药物有可能将患者的发病率和死亡率降至最低，优化同种异体移植的存活率，将再次移植的风险降至最低，并降低与终末期器官衰竭相关的医疗成本。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it aims to conduct mechanistically driven studies to optimize the implementation of immunosuppression in general, and belatacept (costimulation blockade) in particular, as an alternative strategy to prevent rejection following organ transplantation. Proper selection of immunosuppression offers the potential to minimize patient morbidity and mortality, optimize allograft survival, minimize the risk of re-transplantation, and reduce the healthcare costs associated with end stage organ failure.