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: 8102989
• 负责人: JOHN F MCDYER
• 金额: $ 7.38万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102989
• 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; 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; Interferons; Knowledge; Laboratories; Lung; Lung Transplantation; MHC Class I Genes; Measures; Memory; Modeling; Molecular; Monitor; Mononuclear; 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; TNF gene; 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（由申请人提供）：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）相关，供体+/受体- (D+R-) 不匹配的肺移植受者 (LTR) 患 CMV 疾病的风险最高，死亡率增加。 D+R-LTR 发展和维持保护性 CMV 特异性 T 细胞免疫的机制，特别是在肺同种异体移植物中，仍不完全清楚。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 型免疫的核心调节因子）显着诱导。我们的中心假设指出，最佳保护性 CMV 特异性效应记忆 (TEM) 是 T-bet 依赖性/多功能的，对于急性和慢性感染期间肺部和其他组织中的病毒宿主防御是必需的。为了检验这一假设，在 SA1 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。由于我们在主动感染期间意外地在人和小鼠肺气道中检测到了 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，我们将确定在没有抗病毒治疗的情况下，CMV 特异性 T-bet+TEM 细胞反应的差异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 CMV 特异性免疫研究的延伸和扩展，该研究目前由 P1 和他的团队在 D+R-LTR 中根据活跃的 R21 奖项 (R21 A1072537-O1A1) 进行。首席研究员 John McDyer 医学博士是 K08 获奖者、移植肺病学家和免疫学家，致力于了解肺移植受者 CMV 发病机制、病毒免疫和 CMV 感染治疗。他组建了一个由病毒学、生物统计学、流式细胞术/CMV 免疫领域的合作者/顾问组成的专家团队，并在实验室建立了小鼠 CMV (MCMV) 感染模型，以补充人体研究并进一步测试 MCMV 宿主防御机制。该奖项将为独特的人类 CMV 感染模型中的新颖转化工作奠定基础，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。提高对高风险 LTR 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（尤其是肺移植受者）中最常见的感染，与器官同种异体移植排斥和死亡风险增加相关，但原因尚不清楚。了解急性感染期间和之后宿主对 CMV 的免疫反应，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。新知识可能会提高监测高危患者并制定新治疗策略的能力，从而可能为肺移植或其他实体器官移植受者带来更好的结果。