CMV Replication During Primary Infection in Lung Transplant Recipients

肺移植受者原发感染期间 CMV 复制

• 批准号: 7684797
• 负责人: JOHN F MCDYER
• 金额: $ 8.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684797
• 关键词: Acute; Address; Allografting; Antigens; Award; Biological Assay; Biometry; Blood; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4/CD8 ratio procedure; CD8B1 gene; Cells; Chronic; Clinical; Commit; Communicable Diseases; Cytomegalovirus; Cytomegalovirus Infections; DNA; Data; Detection; Development; Diagnosis; Disease; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Foundations; Frequencies; Functional disorder; Goals; Human; Immune; Immune response; Immunodominant Antigens; Immunologist; Infection; Life; Lung; Lung Transplantation; MHC Class I Genes; Measures; Modeling; Opportunistic Infections; Organ Transplantation; Outcome; Pathogenesis; Pathology; Patients; Peptides; Pilot Projects; Plasma; Pneumonia; Publishing; Relative (related person); Research Personnel; Resolution; Risk; Risk Factors; Severities; Solid; Syndrome; System; T-Lymphocyte; Testing; Time; Tissues; Transplant Recipients; Transplantation; Viral; Viral Load result; Work; base; clinically relevant; cohort; high risk; improved; lung allograft; mortality; novel; public health relevance; response; treatment strategy

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Active CMV infection, including CMV pneumonitis, is associated with acute rejection episodes and is a recognized risk factor for chronic rejection (bronchiolitis obliterans syndrome) through poorly understood mechanisms. Donor+/Recipient(D+R-)- mismatched LTRs are at highest risk for CMV disease and demonstrate increased mortality. Moreover, the pathogenesis of active CMV infection and factors associated with clinical severity, such as pneumonitis remain poorly understood. The central hypothesis of this proposal is that both viral replication in the allograft and the host adaptive T cell response regulate the development of CMV pneumonitis and its clinical severity. Our preliminary data show that CMV viral load is higher in the lung airways (bronchoalveolar lavage; BAL) compared to the plasma during primary infection. Therefore, In SA1 we will further validate that replication is increased in the allograft compared to the blood during primary infection. We will also test our hypothesis that BAL viral loads are increased in LTRs with pneumonitis compared to those without. We will also determine whether BAL viral loads are higher with worse clinical severity, using a novel acute lung allograft dysfunction grading system that we have developed. Because we detect a massive influx of CMV-specific CD8+ T cells into the lung airways during pneumonitis, we will further determine in SA2 whether the magnitude of the host CD8+ response to CMV is increased during pneumonitis, and whether the CD8+ T cell response positively correlates with BAL and/or plasma viral loads and acute allograft dysfunction during primary infection. These CMV-specific immune studies are already being conducted in D+R- LTRs by the PI under an R21 award (R21 AI072537-01A1). The PI, John McDyer, MD, is a K08 awardee, transplant pulmonologist, and immunologist, who is strongly committed to understanding pathogenesis of CMV infection and disease in lung transplant recipients. He has assembled an expert team of co-investigators/consultants in transplant infectious disease, biostatistics, and post-transplant lung pathology for this project. This award will provide a foundation for novel translational work in a robust human primary infection model of CMV in LTRs to address these clinically relevant issues. PUBLIC HEALTH RELEVANCE: Solid organ transplantation, including lung transplantation, saves many lives each year. Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients, and is associated with increased risk for both acute and chronic rejection, and increased mortality, though it is unclear why. Understanding CMV replication in conjunction with the host immune response to CMV infection, and clinical measures of severity in susceptible lung transplant recipients may improve our detection of CMV infection, as well as potentially impact treatment strategies and long-term outcomes in all 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感染，尤其是在肺移植受者（LTRS）中。活性CMV感染，包括CMV肺炎，与急性排斥发作有关，是通过较知的理解机制来公认的慢性排斥反应（支气管炎闭塞剂）的危险因素。供体+/受体（D+R-） - 不匹配的LTRS患CMV疾病的风险最高，并且死亡率增加。此外，活动性CMV感染的发病机理以及与临床严重程度相关的因素（例如肺炎）仍然了解不足。该提议的中心假设是同种异体移植中的病毒复制和宿主自适应T细胞反应调节CMV肺炎的发展及其临床严重程度。我们的初步数据表明，与原发性感染期间的血浆相比，肺气道（支气管肺泡灌洗； BAL）中的CMV病毒负荷更高。因此，在SA1中，我们将进一步验证同种异体移植物与原发性感染期间血液相比的复制增加。我们还将检验我们的假设，即与没有肺炎的LTR相比，LTRS中的BAL病毒负荷增加。我们还将使用我们已经开发的新型急性肺同种异体移植功能障碍分级系统来确定bal病毒负荷是否较高，临床严重程度更高。由于我们在肺炎期间检测到CMV特异性CD8+ T细胞大量涌入到肺气道中，因此我们将进一步确定SA2中的宿主CD8+对CMV的大小是否在肺炎过程中增加，以及CD8+ T细胞在肺炎期间是否增加了CD8+ T细胞的响应是否会与BAL和/plasma Viral Pradical and Oriction Allovers and Offerction AllictiCTICTICTICT ARTICTICT ALRICTICT相关。 PI根据R21奖（R21 AI072537-01A1）在D+R-LTR中已经在D+R-LTR中进行了这些CMV特异性免疫研究。 PI，John McDyer，医学博士是K08获奖者，移植肺科医生和免疫学家，他强烈致力于了解肺移植受者中CMV感染和疾病的发病机理。他召集了一个由移植传染病，生物统计学和移植后肺部病理学的共同投资者/顾问组成的专家团队。该奖项将为LTR中CMV的强大人类主要感染模型的新型翻译工作提供基础，以解决这些临床相关问题。 公共卫生相关性：固体器官移植，包括肺移植，每年挽救许多生命。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，并且与急性和慢性排斥的风险增加以及死亡率增加有关，尽管目前尚不清楚为什么。了解CMV复制与宿主对CMV感染的免疫反应以及易感肺移植受者严重程度的临床测量可能会改善我们对CMV感染的检测，并可能影响所有固体器官移植者的治疗策略和长期结局。

项目成果

Phenotypic and functional characterization of cytotoxic T lymphocytes by flow cytometry.

通过流式细胞术表征细胞毒性 T 淋巴细胞的表型和功能。

• DOI: 10.1007/978-1-4939-1158-5_3
• 发表时间: 2014
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Popescu,Iulia;Pipeling,Matthew;Akulian,Jason;McDyer,John
• 通讯作者: McDyer,John

The big picture: A case report of antibody mediated rejection and treatment after lung transplantation illustrating the need to correlate laboratory findings with clinical status.

总体情况：肺移植后抗体介导的排斥和治疗的病例报告说明需要将实验室检查结果与临床状态相关联。

• 发表时间: 2013
• 期刊: Clinical transplants
• 作者: Zeevi,Adriana;Marrari,Marilyn;Lunz,John;Lomago,Jon;Johnson,Kurt;Jelinek,Lawrence;Foster,Donald;Bermudez,Christian;McDyer,John;Pilewski,Joseph;Ensor,Christopher
• 通讯作者: Ensor,Christopher