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

描述（由申请方提供）：巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者（LTR）中最常见的机会性感染。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）相关，供体+/受体-（D+R-）不匹配的肺移植受体（LTR）发生CMV疾病的风险最高，死亡率增加。D+ R-LTR产生和维持保护性CMV特异性T细胞免疫的机制，特别是在肺同种异体移植物内，仍然不完全清楚。我们的初步数据显示，在人类原发性CMV感染期间，转录因子T-bet（小鼠1型免疫的中央调节因子）显著诱导。我们的中心假设指出，最佳的保护性CMV特异性效应记忆（TEM）是T-bet依赖性/多功能的，并且是急性和慢性感染期间肺和其他组织中病毒宿主防御所必需的。为了验证这一假设，在SA 1中，我们将确定T-bet在人类和小鼠CMV感染期间调节TEM细胞功能和宿主防御中的作用。由于我们在活动性感染期间意外地在人和小鼠肺气道中检测到CMV特异性CCR 7 + TCM细胞，我们将确定TCM和T-bet+TEM细胞之间的关系，以及TCM细胞在SA 2中肺宿主防御中的作用。我们的初步数据表明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，我们将确定在没有抗病毒治疗的情况下，CMV特异性T-bet+TEM细胞应答差异是否预测急性原发性/短期与长期CMV保护。我们的提案是对目前由Pl和他的团队在活跃的R21奖项（R21 A1072537-O 1 A1）下在D+ R-LTR中进行的CMV特异性免疫研究的扩展和扩展。PI，John McDyer，MD，是K 08获奖者，移植肺病学家和免疫学家，他致力于了解肺移植受者中CMV感染的发病机制，病毒免疫和治疗。他组建了一个由病毒学、生物统计学、流式细胞术/CMV免疫方面的合作者/顾问组成的专家团队，并在他的实验室建立了一个小鼠CMV（MCMV）感染模型，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，并沿着MCMV模型研究，解决病毒宿主防御中的临床相关问题。对高危LTR中CMV特异性免疫的了解和分析的提高可能会增强我们对这些具有挑战性的患者进行风险分层的临床能力，并可能影响未来的抗病毒治疗实践。 公共卫生相关性：巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者中最常见的感染，与器官移植排斥反应和死亡率的风险增加有关，但原因尚不清楚。了解急性感染期间和之后对CMV的宿主免疫反应，以及调节移植受者这些反应的因素，将提高我们对CMV感染和免疫的认识。新的知识可能会提高监测高危患者的能力，并制定新的治疗策略，可能会导致肺移植或其他实体器官移植受者的更好结果。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients, and is associated with increased risk for organ allograft rejection and mortality, though it is unclear why. Understanding the host immune response to CMV during and after acute infection, and the factors that regulate these responses in transplant recipients, will improve our knowledge of CMV infection and immunity. New knowledge may improve the ability to monitor high-risk patients and develop new treatment strategies, perhaps leading to better outcomes in lung transplant or other solid organ transplant recipients.