CMV-Specific T-Cell Immunity in Lung Transplant Recipients

描述（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，特别是在肺移植受者（lts）中。我们发表的数据显示，CMV高风险的供体阳性/受体阴性LTRs （D+R-）经常发生CMV特异性免疫反应，通常在初次感染后很长一段时间内，CMV特异性效应记忆T细胞在肺移植和血液中持续存在。利用我们的新系统来鉴定支气管肺泡灌洗获得的同种异体移植细胞（allograft BAL细胞）和外周血单核细胞（PBMC）中的CMV特异性T细胞，这一建议将扩展我们之前的工作，并更密切地检查这些不同组织室中的CMV记忆池。我们发表的观察结果表明，在PBMC中检测不到CMV特异性CD4+ T细胞，但在BAL细胞中可以检测到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中使用多种CMV抗原、CMV I类四聚体和多参数流式细胞分析进行探讨。由于大多数D+R- LTRs发生活动性巨细胞病毒感染，我们将验证我们的假设，即在SA2的肺同种异体移植和PBMC中，巨细胞病毒特异性细胞反应在从活动性原发性感染到潜伏性感染的转变过程中发生变化。我们令人兴奋的初步数据显示，我们在6个D+R- ltr中前瞻性地捕获了两个组织区室中强大的cmv特异性T细胞新生反应。据推测，mhc错配屏障可能限制巨细胞病毒宿主的防御，特别是在同种异体移植物水平上。使用低温保存的供体脾细胞或PBMC，我们将测试LTRs在供体抗原呈递细胞（APC）的背景下表现cmv特异性效应反应的能力，并将其与SA3中自体APC进行比较。PI， John McDyer医学博士，K08奖获得者和助理教授，是约翰霍普金斯大学肺/危重症医学部的移植肺病学家和niaid训练的免疫学家，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转化研究提供基础，研究巨细胞病毒、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巨细胞病毒特异性T细胞记忆的认识及其在移植中的潜在临床意义。巨细胞病毒（CMV）是实体器官移植受者最常见的感染，尤其是肺移植受者。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巨细胞病毒感染的免疫反应可以改善我们的治疗策略，并最终影响移植受者的长期预后。

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.