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

肺移植受者 CMV 特异性 T 细胞记忆的发展

• 批准号: 7886599
• 负责人: JOHN F MCDYER
• 金额: $ 40.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886599
• 关键词: Active Sites; Acute; Address; Adoptive Transfer; Allografting; Antigens; Antiviral Therapy; Award; Biological Assay; Biometry; Blood; Bronchiolitis Obliterans; Bronchoalveolar Lavage; CD8B1 gene; Cell Culture System; Cell Separation; Cell physiology; Cells; Chronic; Clinical; Commit; Complement; Congenic Mice; Contracts; Cytomegalovirus; Cytomegalovirus Infections; D Cells; Data; Decision Making; Development; Disease; Employee Strikes; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Flow Cytometry; Foundations; Functional disorder; Future; Genes; Host Defense; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunologist; In Vitro; Infection; Injury; Knowledge; Laboratories; Lung; Lung Transplantation; MHC Class I Genes; Measures; Memory; Modeling; Molecular; Monitor; Murid herpesvirus 1; Mus; Opportunistic Infections; Organ Transplantation; Outcome; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Publishing; Recurrence; Regulation; Relapse; Risk; Role; Site; Solid; Staining method; Stains; Study models; Syndrome; T cell response; T memory cell; T-Lymphocyte; T-bet protein; Testing; Time; Tissues; Transgenic Mice; Transplant Recipients; Transplantation; Viral; Viral Load result; Viral Pathogenesis; Viremia; Virus Diseases; Work; adaptive immunity; allograft rejection; base; clinically relevant; cytokine; high risk; improved; in vivo; lung allograft; mortality; novel; peripheral blood; public health relevance; response; terminally differentiated effector memory (TEM) T cells; trafficking; treatment strategy; virology

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.

描述(申请人提供)：巨细胞病毒(CMV)是实体器官移植受者，尤其是肺移植受者最常见的机会性感染。活动性巨细胞病毒感染与急性和慢性排斥反应(闭塞性毛细支气管炎综合征)有关，供体+/受体(D+R-)不匹配的肺移植受者患巨细胞病毒病的风险最高，死亡率也会增加。D+R-LTRs发展和维持保护性CMV特异性T细胞免疫的机制仍不完全清楚，尤其是在同种异体肺移植中。我们的初步数据显示，在人类原发CMV感染过程中，转录因子T-bet显著诱导，T-bet是小鼠1型免疫的中央调节因子。我们的中心假说表明，最佳保护性CMV特异性效应记忆(TEM)是T依赖的/多功能的，是急、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SA1中，我们将确定T-bet在人和小鼠CMV感染过程中对TEM细胞功能和宿主防御的调节作用。由于我们在活动性感染期间在人和小鼠肺内意外检测到CMV特异性CCR7+Tcm细胞，因此我们将确定Tcm与T-bet+Tm细胞的关系，以及Tcm细胞在SA2肺宿主防御中的作用。我们的初步数据表明，CMV特异性CD8+T细胞记忆的免疫优势随着时间的推移而变化。在SA3中，我们将确定在缺乏抗病毒治疗的情况下，不同的CMV特异性T-bet+TEM细胞反应是否可以预测急性初级/短期与长期CMV保护。我们的建议是对目前由PL和他的团队在活跃的R21奖(R21 A1072537-O1A1)下在D+R-LTRS进行的CMV特异性免疫研究的延伸和扩展。约翰·麦克代尔医学博士是K08获奖者、移植肺病学家和免疫学家，他坚定地致力于了解CMV的发病机制、病毒免疫和肺移植受者CMV感染的治疗。他组建了一支病毒学、生物统计学、流式细胞术/巨细胞病毒免疫方面的合作者/顾问专家团队，并在他的实验室建立了小鼠巨细胞病毒(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。该奖项将为一种独特的人类CMV感染模型的新颖翻译工作提供基础，并与MCMV模型研究一起，解决病毒宿主防御中的临床相关问题。提高对高危LTRS中CMV特异性免疫的了解和分析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，特别是肺移植受者最常见的感染，并与器官移植排斥反应和死亡的风险增加有关，尽管原因尚不清楚。了解在急性感染过程中和急性感染后宿主对CMV的免疫反应，以及调节这些反应的因素，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，并开发新的治疗策略，或许会导致肺移植或其他固体器官移植接受者获得更好的结果。