Defining Protective CMV Immunity after Transplantation

项目总结/摘要 巨细胞病毒（CMV）感染是一种常见的和危及生命的并发症，显着限制了 同种异体造血干细胞或骨髓移植（下文中提及）成功结果 在BMT）。我们最近开发了长期期望的骨髓移植后CMV再激活的临床前（鼠）模型 并首次证明了体液免疫对防止病毒复发至关重要。我们现在展示 免疫T细胞或菌株特异性血清（含有IgG抗体）的转移可以防止病毒感染。 移植物抗宿主病（GVHD）期间的再激活、病毒血症、终末器官病毒复制和巨细胞病毒病。我们 计划利用我们独特的，但完善的临床前模型，以确定保护性抗体对 CMV再激活、传播和抗原呈递的时空特征。 随后，我们将定义持久控制所需的T细胞和体液反应的相互作用。 骨髓移植后巨细胞病毒再激活的可能性。最后，我们将开发临床上易于处理的途径来增强CMV免疫力 同时预防GVHD和相关炎症，靶向IL-6抑制。我们建议的研究将提供 对GVHD受者有效和长期控制CMV的免疫要求的重要见解 和/或临床相关的免疫抑制和炎症，这将使我们能够优化CMV免疫， 临床BMT，以改善患者的预后。

PROJECT SUMMARY/ABSTRACT Cytomegalovirus (CMV) infection is a frequent and life-threatening complication that significantly limits the successful outcome of allogeneic hematopoietic stem cell or bone marrow transplantation (referred to hereafter at BMT). We have recently developed long-desired preclinical (murine) models of CMV reactivation after BMT and show for the first time, that humoral immunity is critical to prevent viral recrudescence. We now demonstrate that either the transfer of immune T cells or strain-specific sera (containing IgG antibody) prevents viral reactivation, viremia, end-organ viral replication and CMV disease during graft-versus-host disease (GVHD). We plan to utilize our unique, but well-established preclinical models to define the impact of protective antibody on the temporal and spatial characteristics of CMV reactivation, dissemination and antigen presentation. Subsequently we will define the interplay of T cell and humoral responses that are required for the durable control of CMV reactivation after BMT. Finally, we will develop clinically tractable pathways to enhance CMV immunity whilst preventing GVHD and associated inflammation, targeting IL-6 inhibition. Our proposed studies will provide critical insights into the immune requirements for effective and long-term control of CMV in recipients with GVHD and/or clinically relevant immune suppression and inflammation that will allow us to optimize CMV immunity in clinical BMT to improve patient outcomes.