Development of CMV-specific T Cell Memory in Lung Transplant Recipients

摘要： 巨细胞病毒（CMV）是实体器官移植受者中最常见的机会性感染， 特别是在肺移植受者（LTR）中。活动性CMV感染与急性和慢性 排斥反应（闭塞性细支气管炎综合征），供体+/受体-（D+R-）不匹配的肺移植受者 （LTR）CMV疾病的风险最高，死亡率增加。D+ R-LTR形成的机制 并维持保护性CMV特异性T细胞免疫，特别是在肺同种异体移植物中， 明白我们的初步数据揭示了一个引人注目的诱导转录因子T-bet，一个中央调节器 1型免疫小鼠，在人类原发性CMV感染。我们的中心假设是， 保护性CMV特异性效应记忆（TEM）是T-bet依赖性/多功能的，并且是病毒感染所必需的。 在急性和慢性感染期间，肺和其他组织中的宿主防御。为了验证这一假设，在 SA 1我们将确定T-bet在人类免疫过程中调节TEM细胞功能和宿主防御中的作用。 和鼠CMV感染。因为我们意外地在人类中检测到CMV特异性CCR 7 + TCM细胞， 本研究通过对小鼠活动性感染时肺气道的动态观察，探讨TCM与T-bet+TEM的关系 细胞，以及TCM细胞在SA 2.我们的初步数据显示 CMV特异性CD 8 + T细胞记忆的免疫优势随时间变化。在SA 3中，我们将确定是否 CMV特异性T-bet+TEM细胞应答差异预测急性原发/短期vs长期CMV 在没有抗病毒治疗的情况下提供保护。我们的建议是一个扩展和扩展的CMV的具体 免疫研究，目前正在进行的D+R-LTR下，由PI和他的团队在一个积极的R21奖 (R21 A1072537-O1A1）。PI，医学博士John McDyer，是K 08获奖者，移植肺病学家， 免疫学家，他坚定地致力于了解CMV发病机制，病毒免疫和治疗， 肺移植受者巨细胞病毒感染。他组建了一个由合作者/顾问组成的专家团队， 病毒学，生物统计学，流式细胞术/CMV免疫，并建立了小鼠CMV（MCMV）模型， 感染，以补充人类研究和进一步测试MCMV宿主防御机制。 该奖项将为独特的人类CMV感染模型中的新型翻译工作提供基础， 沿着MCMV模型研究，解决病毒宿主防御中的临床相关问题。改进知识 对高危LTR中CMV特异性免疫的分析可能会提高我们对这些疾病进行风险分层的临床能力。 挑战患者，并可能影响未来的抗病毒治疗实践。

Abstract: Cytomegalovirus (CMV) is the most common opportunistic infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Active CMV infection is associated with acute and chronic rejection (bronchiolitis obliterans syndrome), with donor+/recipient- (D+R-) mismatched lung transplant recipients (LTRs) at highest risk for CMV disease and increased mortality. The mechanisms by which D+R- LTRs develop and maintain protective CMV-specific T cell immunity, particularly within the lung allograft, remain incompletely understood. Our preliminary data reveal a striking induction of the transcription factor T-bet, a central regulator of Type-1 immunity in mice, during human primary CMV infection. Our central hypothesis states that optimal protective CMV-specific effector memory (TEM) is T-bet-dependent/polyfunctional, and necessary for viral host defense in the lung and other tissues during acute and chronic infection. To test this hypothesis, in SA1 we will determine the role of T-bet in the regulation of TEM cell function and host defense during human and murine CMV infection. Because we unexpectedly detect CMV-specific CCR7+ TCM cells in human and murine lung airways during active infection, we will determine the relationship between TCM and T-bet+TEM cells, and the role of TCM cells in pulmonary host defense in SA2. Our preliminary data indicates the immunodominance of CMV-specific CD8+ T cell memory changes over time. In SA3, we will determine whether differential CMV-specific T-bet+TEM cell responses predict acute primary/short-term versus long-term CMV protection in the absence of antiviral therapy. Our proposal is an extension and expansion of CMV-specific immune studies currently being conducted in D+R- LTRs by the Pl and his team under an active R21 award (R21 A1072537-O1A1). The PI, John McDyer, MD, is a K08 awardee, transplant pulmonologist, and immunologist, who is strongly committed to understanding CMV pathogenesis, viral immunity, and treatment of CMV infection in lung transplant recipients. He has assembled an expert team of collaborators/consultants in virology, biostatistics, flow cytometry/CMV immunity, and has established a murine CMV (MCMV) model of infection in his laboratory to complement human studies and further test mechanisms in MCMV host defense. This award will provide a foundation for novel translational work in a unique human CMV infection model, and along with MCMV model studies, address clinically relevant issues in viral host defense. Improved knowledge and analysis of CMV-specific immunity in high-risk LTRs may enhance our clinical ability to risk-stratify these challenging patients, and potentially impact future antiviral therapy practices.