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）：器官移植的可观益处被与其所需的慢性免疫抑制疗法相关的并发症显着抵消。患者通常使用几种药物，但是钙调神经酶抑制剂（CNIS）长期以来一直是大多数方案的核心。 CNIS有效防止排斥反应，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和许多非免疫副作用有关。今年，已批准了CNI替代方案：Belatacept，一种融合蛋白，介导CD28-B7共刺激阻滞（COB）。大量的临床证据表明，Belatacept可以用作CNI替代品，避免CNI特异性脱靶副作用。然而，在某些情况下，Belatacept似乎较低，无法防止排斥，并且不会造成病毒免疫力，尤其是对普通的爱泼斯坦 - Barr病毒。因此，临床医生现在采用了两种不同的方法来防止移植排斥，基于CNI和COB的免疫抑制，但很少数据指导它们之间的合理选择。该应用在移植，CNI/BELATACEPT选择及其与拒绝和病毒感染的相互并发症的关系方面遇到了这种高度当代的困境。我们假设通过一个被称为异源的同种免疫性 - 抗气免疫性的过程与先前的病毒感染成熟，并且T细胞表型在整个生命中出现并影响同种和病毒免疫性的变化可以预测，可以预期一个人对CNIS和COB的反应。我们认为，这些表型变化可用于开发一种具有生物学上合理的，治疗性相关和可诊断性的可定义方法，以隔离那些将从基于Belatacept的方案中受益的患者与基于CNI的方法更好地服务的患者。我们在三个特定目标中探讨了这一假设，一项在人类中进行的观察性研究来定义与肾脏移植者的T细胞分化和疲惫有关的程度，在基于CNI-或BELATACEPT的疗法的背景下，以及使用临床相关的，临床相关的，临床相关的机构效果的实验性项目，以及两个实验性项目，并建立了临床相关的效果。同种和病毒特异性免疫。为这项研究成立的调查团队易于使用移植患者的观察来告知严格控制动物研究的行为，并使用新型动物实验来修改人类研究。它集中在一个高容量移植中心，该中心开发了出色的基础设施，用于获取良好的人类样品，并为接受基于CNI-和Belatacept的治疗方案的患者提供了非凡的接触。因此，每个目标都将被认识到相关的临床环境和机械原理。这项研究将促进统一的范式的发展，以指导免疫抑制剂的合理选择，并促进针对移植患者的个性化，数据驱动的免疫管理。 公共卫生相关性：拟议的研究与公共卫生有关，因为它旨在进行机械驱动的研究，以优化一般的免疫抑制实施，尤其是Belatacept（Costimulation Bossade），作为防止器官移植后拒绝的替代策略。正确选择免疫抑制，可以最大程度地减少患者的发病率和死亡率，优化同种异体移植物的生存，最大程度地减少重新转移的风险，并降低与终阶段器官衰竭相关的医疗保健成本。