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，尤其是肺移植受者最常见的机会性感染。我们发表的数据显示，CMV高风险的供者阳性/受体阴性LTRS(D+R-)经常产生CMV特异性免疫反应，通常在初次感染后很长一段时间内同种异体肺移植和血液中CMV特异性效应记忆T细胞持续存在。使用我们的新系统在支气管肺泡灌洗获得的同种异体移植细胞(同种异体BAL细胞)和外周血单个核细胞(PBMC)中识别CMV特异性T细胞，该提议将扩展我们之前的工作，并更密切地检查这些不同组织间隔中的CMV记忆池。我们发表的观察结果表明，在BAL细胞中可以区别检测到CMV特异性的CD4+T细胞，而在PBMC中检测不到，这使得我们假设同种异体移植物中CMV记忆细胞的频率、表型和功能与PBMC相比有所不同。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索这一点。由于大多数D+R-LTRs发展为活动性CMV感染，我们将检验我们的假设，即在肺移植物和SA2中的PBMC中，CMV特异性细胞反应在从活动性原发感染向潜伏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，我们预期在6个D+R-LTrs中捕获的两个组织间隔中都有强大的从头开始的CMV特异性T细胞反应。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水平上。使用冷冻保存的供体脾细胞或PBMC，我们将在供体抗原提呈细胞(APC)的背景下与SA3中的自体APC比较，测试LTRS展示CMV特异性效应反应的能力。约翰·麦克代尔医学博士，K08获奖者和助理教授，是约翰霍普金斯大学肺/重症监护医学部的移植肺病专家，也是NIAID培训的免疫学家，致力于促进我们对移植免疫生物学和与移植相关的宿主防御领域的理解。这项R21奖将为未来以患者为基础的转化性研究奠定基础，该研究将检验CMV、同种异体移植物和宿主免疫系统之间的动态关系，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尤其是肺移植受者最常见的感染。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进我们的治疗策略，并最终影响移植受者的长期结果。

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.