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

T 细胞成熟以及病毒免疫和同种异体免疫的关系

• 批准号: 8371823
• 负责人: Allan D. Kirk
• 金额: $ 52.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371823
• 关键词: Acute; Adverse effects; Age; Allografting; Animal Experiments; Antigens; Antiviral Agents; Attention; Automobile Driving; Back; Benefits and Risks; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Calcineurin inhibitor; Cardiac; Cardiovascular system; Cell Adhesion Molecules; Cell Maturation; Characteristics; Chimeric Proteins; Chronic; Clinical; Control Animal; Cross-Sectional Studies; Data; Dependence; Development; Dialysis procedure; Drug usage; Equilibrium; Etiology; Evolution; Exposure to; FDA approved; Gap Junctions; Graft Rejection; Health Care Costs; Herpesviridae; Homologous Gene; Human; Human Herpesvirus 4; Immune; Immunity; Immunosuppression; Immunosuppressive Agents; Impairment; Improve Access; Indolent; Infection; Kidney; Kidney Transplantation; Life; Longitudinal Studies; Lymphocyte; Maintenance; Malignant - descriptor; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Observational Study; Organ; Organ Transplantation; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Process; Property; Public Health; Regimen; Research; Research Infrastructure; Research Personnel; Risk; Sampling; Skin; Specific qualifier value; T cell differentiation; T cell response; T-Lymphocyte; Tacrolimus; Testing; Therapeutic immunosuppression; Toxic effect; Transplant Recipients; Transplantation; Up-Regulation; Viral; Virus Diseases; Virus Latency; Withdrawal; allograft rejection; base; clinically relevant; diabetic; end-stage organ failure; exhaust; exhaustion; experience; in vivo; interest; isoimmunity; mortality; mouse model; novel; prevent; research study; response; senescence

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.

描述（由申请人提供）：器官移植的巨大益处被与其所需的长期免疫抑制治疗相关的并发症所抵消。患者通常服用多种药物，但钙调神经磷酸酶抑制剂 (CNI) 长期以来一直是大多数治疗方案的核心。 CNI 可以有效防止排斥反应，但其使用会导致非抗原特异性 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。今年，一种 CNI 替代品已获得批准：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可以作为CNI替代品，避免CNI特异性的脱靶副作用。然而，贝拉西普在某些情况下似乎不太能防止排斥反应，并且会不均匀地损害病毒免疫力，特别是针对常见的 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，即基于 CNI 和 CoB 的免疫抑制，但指导合理选择的数据却很少。该应用解决了移植中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相互并发症的关系。我们假设排斥和病毒感染通过一种称为异源同种免疫的过程（通过先前的病毒感染成熟的同种免疫）在机制上相关，并且已知在整个生命中出现并影响同种免疫和病毒免疫的 T 细胞表型变化可用于预测一个人对 CNI 和 CoB 的反应。我们相信这些表型变化可用于开发一种生物学上合理的、治疗上相关的和诊断上可定义的方法，将那些将从基于贝拉西普的治疗方案中受益的患者与那些通过基于 CNI 的方法更好地服务的患者分开。我们在三个具体目标中探讨了这一假设，其中一项是在人体中进行的观察性研究，旨在确定在基于 CNI 或贝拉西普的治疗背景下，病毒感染和排斥与肾移植受者 T 细胞分化和耗竭相关的程度，以及两个使用明确的、临床相关的移植和病毒感染小鼠模型进行的实验项目，以确定 CNI 和 CoB 特异性影响的机制。 同种异体和病毒特异性免疫。为这项研究组建的调查小组很容易利用移植患者的观察结果来指导严格控制的动物研究的进行，并利用新颖的动物实验来修改人类研究。它以一个大容量移植中心为中心，该中心开发了出色的基础设施，用于获取特征良好的人体样本，并特别接触接受基于 CNI 和贝拉西普的治疗方案的患者。因此，每个目标的实施都将考虑到相关的临床情况和机制原理。这项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，并促进移植患者的个体化、数据驱动的免疫管理。 公共健康相关性：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，以优化一般免疫抑制的实施，特别是贝拉西普（共刺激阻断），作为预防器官移植后排斥反应的替代策略。正确选择免疫抑制可以最大限度地降低患者的发病率和死亡率，优化同种异体移植物的存活率，最大限度地降低再移植的风险，并降低与终末期器官衰竭相关的医疗费用。