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（由申请方提供）：巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者（LTR）中最常见的机会性感染。我们发表的数据显示，CMV高危的供体阳性/受体阴性LTR（D+R-）经常发生CMV特异性免疫应答，通常在初次感染后很长时间内，CMV特异性效应记忆T细胞在肺移植物和血液中持续存在。使用我们的新系统来识别支气管肺泡灌洗获得的同种异体移植细胞（同种异体移植BAL细胞）和外周血单核细胞（PBMC）中的CMV特异性T细胞，该建议将扩展我们以前的工作，并更密切地研究这些不同组织隔室中的CMV记忆池。我们发表的观察结果表明，CMV特异性CD 4 + T细胞可以在BAL细胞中差异检测到，而在PBMC中检测不到，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SA 1中使用多种CMV抗原、CMV I类四聚体和多参数流式细胞术分析进行探索。由于大多数D+ R-LTR发生活动性CMV感染，我们将检验我们的假设，即在SA 2中，肺同种异体移植物和PBMC从活动性原发感染转变为潜伏感染期间，CMV特异性细胞反应发生变化。我们令人兴奋的初步数据显示了我们在6个D+ R-LTR中前瞻性捕获的两个组织区室中的稳健的从头CMV特异性T细胞应答。据推测，MHC错配屏障可能会限制CMV宿主的防御，特别是在同种异体移植物的水平。使用低温保存的供体脾细胞或PBMC，我们将测试与SA 3中的自体APC相比，LTR在供体抗原呈递细胞（APC）的背景下表现出CMV特异性效应子应答的能力。PI，John McDyer医学博士，K 08获奖者和助理教授，是约翰霍普金斯肺/重症监护医学部的移植肺病学家，也是NIAID培训的免疫学家，致力于推进我们对移植免疫生物学和移植相关宿主防御领域的理解。该R21奖项将为未来基于患者的翻译研究提供基础，研究CMV，同种异体移植物和宿主免疫系统之间的动力学，这可能会增加我们对CMV特异性T细胞记忆及其在移植中的潜在临床意义的了解。巨细胞病毒（CMV）是实体器官移植受者，特别是肺移植受者中最常见的感染。巨细胞病毒感染与肺移植受者急性和慢性排斥反应的风险增加有关，尽管原因尚不清楚。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。