CMV-Specific T-Cell Immunity in Lung Transplant Recipients

肺移植受者的 CMV 特异性 T 细胞免疫

• 批准号: 7256864
• 负责人: JOHN F MCDYER
• 金额: $ 24.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256864
• 关键词: CMV; Specific; Cell; Immunity; Lung

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) is the most common opportunistic infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Our published data show that donor positive/recipient negative LTRs (D+R-) at high risk for CMV frequently develop CMV-specific immune responses, often with a persistence of CMV-specific effector memory T cells in the lung allograft and blood long after primary infection. Using our novel system to identify CMV-specific T cells in bronchoalveolar lavage-obtained allograft cells (allograft BAL cells) and peripheral blood mononuclear cells (PBMC), this proposal will extend our previous work and examine more closely the CMV memory pools in these distinct tissue compartments. Our published observation that CMV-specific CD4+ T cells can be differentially detected in the BAL cells when undetectable in the PBMC, has led us to hypothesize that there are differences in the frequency, phenotype and function of CMV memory cells in the allograft compared to PBMC. This will be explored in SA1 using a variety of CMV antigens, CMV class I tetramers and multi-parameter flow cytometric analysis. Because the majority of D+R- LTRs develop active CMV infection, we will test our hypothesis that CMV-specific cellular responses change during the transition from active primary infection to latent infection in the lung allograft and PBMC in SA2. Our exciting preliminary data show robust de novo CMV-specific T cell responses in both tissue compartments that we have prospectively captured in 6 D+R- LTRs. It has been postulated that the MHC-mismatch barrier may limit CMV host defense, particularly at the level of the allograft. Using cryogenically preserved donor splenocytes or PBMC we will test the ability of LTRs to exhibit CMV-specific effector responses in the context of donor antigen presenting cells (APC) compared to autologous APC in SA3. The PI, John McDyer MD, a K08 awardee and Assistant Professor, is a transplant pulmonologist in the Johns Hopkins Division of Pulmonary/Critical Care Medicine and an NIAID-trained immunologist committed to advancing our understanding in the field of transplant immunobiology and transplant-related host defense. This R21 award will provide the foundation for future patient-based translational studies examining the dynamics between CMV, the allograft, and host immune system that may increase our knowledge of CMV-specific T cell memory and its potential clinical implications in transplant. Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients. CMV infection is associated with increased risk for both acute and chronic rejection in lung transplant recipients, though it is unclear why. Understanding the immune response to CMV infection in susceptible lung transplant recipients may improve our treatment strategies and ultimately impact long-term outcomes in 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。我们已发表的数据表明，供体阳性/受体负LTR（D+R-）高风险CMV经常会产生CMV特异性免疫反应，通常在初次感染后很长一段时间内肺同种异体移植物和血液中CMV特异性效应记忆T细胞的持久性。使用我们的新系统来鉴定支气管肺泡灌洗细胞中的CMV特异性T细胞（同种异体BAL细胞）和外周血单核细胞（PBMC），此建议将扩展我们以前的工作并更仔细地检查这些不同组织室中的CMV存储库。我们发表的观察结果是，当在PBMC中不可检测时，在BAL细胞中可以差异地检测到CMV特异性CD4+ T细胞，这使我们假设与PBMC相比，同种异体移植物中CMV记忆细胞的频率，表型和功能存在差异。这将在SA1中使用各种CMV抗原，CMV I类四聚体和多参数流式细胞术分析来探讨这一点。由于大多数D+r-LTRS都会发展出活跃的CMV感染，因此我们将测试我们的假设，即CMV特异性细胞反应在SA2中的肺同种异体移植物和PBMC的过渡过程中变化。我们令人兴奋的初步数据表明，在两个组织室中，我们在6 d+r-ltrs中都捕获了从头CMV特异性T细胞反应。据推测，MHC不匹配的屏障可能会限制CMV宿主防御，尤其是在同种异体移植水平上。使用低温供体脾细胞或PBMC，我们将在供体抗原呈递细胞（APC）（APC）的背景下测试LTR与SA3自体APC相比，在供体抗原呈递细胞（APC）中表现出CMV特异性效应子响应的能力。 PI，John McDyer MD是K08获奖者，助理教授，是Johns Hopkins肺部/重症监护医学部的移植肺科医生，也是由NIAID训练的免疫学家，致力于促进我们在移植免疫学领域的理解和与移植相关的主持人国防部。该R21奖将为未来的基于患者的翻译研究奠定基础，研究CMV，同种异体移植和宿主免疫系统之间的动态，这可能会增加我们对CMV特异性T细胞记忆的了解及其对移植中的潜在临床意义。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。 CMV感染与肺移植受体中急性和慢性排斥的风险增加有关，尽管目前尚不清楚为什么。了解易感肺移植受者对CMV感染的免疫反应可能会改善我们的治疗策略，并最终影响移植受者的长期结局。