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: 7662207
• 负责人: JOHN F MCDYER
• 金额: $ 41万
• 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/7662207
• 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 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; 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（由申请人提供）：巨细胞病毒（CMV）是固体器官移植受体中最常见的机会感染，尤其是在肺移植受者（LTRS）中。活性CMV感染与急性和慢性排斥反应（支气管炎抑制剂）有关，供体+/受体 - （D+R-）不匹配的肺移植受者（LTR）对CMV疾病的风险最高和死亡率增加。 D+R-LTRS发展和维持保护性CMV特异性T细胞免疫的机制，尤其是在同种异体移植物中，尚不完全了解。我们的初步数据揭示了人类原发性CMV感染期间，转录因子T-BET T-BET T-BET T-BET T-BET是小鼠中1型免疫的中心调节剂。我们的中心假设指出，最佳保护性CMV特异性效应子记忆（TEM）是T-Bet依赖性/多功能的，对于急性和慢性感染期间，肺和其他组织中的病毒宿主防御所必需。为了检验这一假设，在SA1中，我们将确定T-BET在人和鼠CMV感染期间TEM细胞功能和宿主防御调节中的作用。由于我们在活动感染期间意外地检测到人和鼠肺气道中的CMV特异性CCR7+ TCM细胞，因此我们将确定TCM和T-BET+ TEM细胞之间的关系，以及TCM细胞在SA2中肺部宿主防御中的作用。我们的初步数据表明CMV特异性CD8+ T细胞存储器随时间变化的影响。在SA3中，我们将确定在没有抗病毒疗法的情况下，是否可以预测急性初级/短期/短期CMV保护差异CMV特异性T-BET+TEM细胞反应。我们的提议是PL及其团队目前根据Active R21奖（R21 A1072537-O1A1）在D+R-LTRS中进行CMV特异性免疫研究的扩展和扩展。 PI，John McDyer，医学博士是K08获奖者，移植肺科医生和免疫学家，他强烈致力于理解肺移植受者中CMV发病机理，病毒免疫和CMV感染的治疗。他召集了一支由病毒学，生物统计学，流式细胞仪/CMV免疫的合作者/顾问的专家团队，并在其实验室中建立了一个鼠CMV（MCMV）模型，以补充人类研究和MCMV宿主防御的进一步测试机制。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，以及MCMV模型研究，解决了病毒宿主防御中临床相关问题。对高危LTR中CMV特异性免疫力的知识和分析可以提高我们的临床能力，以使这些具有挑战性的患者风险分层，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）是固体器官移植受者（尤其是肺移植受者）中最常见的感染，并且与增加器官同种异体移植抑制和死亡率的增加有关，尽管目前尚不清楚为什么。了解急性感染期间和之后的宿主对CMV的免疫反应，以及在移植受者中调节这些反应的因素，将提高我们对CMV感染和免疫力的了解。新知识可能会提高监测高危患者并制定新的治疗策略的能力，这可能会导致肺移植或其他固体器官移植受者的更好结果。