Predicting Lung Allograft Rejection Using CMV-Specific T-cell Responses

描述(申请人提供)：巨细胞病毒(CMV)是疱疹病毒科的一种DNA病毒。在初次感染后，CMV变得潜伏，并有可能在未来重新激活潜伏的病毒。巨细胞病毒(CMV)是肺移植后感染性病原体致病的最重要来源，可引起有害的直接影响(肺炎)和间接影响，如对供体肺(同种异体移植)的增强排斥反应。肺移植患者长期存活的限制因素是同种异体移植排斥反应。多项研究证实，CMV感染和排斥反应之间存在很强的相关性。巨细胞病毒特异性T细胞反应在控制巨细胞病毒复制方面非常重要，但在评估巨细胞病毒特异性T细胞免疫在排斥反应中的作用方面研究甚少，尤其是对肺移植。这项建议的中心目标是确定肺移植患者中CMV特异性T细胞反应的测量是否可以用来预测同种异体移植排斥反应和CMV载量控制不良的风险。这项研究的目的是：1.确定循环中CMV特异性T细胞反应是否能预测移植受者对肺移植排斥反应的保护作用。2.探讨同种异体肺移植排斥反应与血液和肺内亚临床CMV感染的关系。3.确定肺中CMV特异性T细胞反应在预测肺移植排斥反应和肺病毒载量下降的保护作用中的作用。对CMV特异性T细胞反应和病毒载量的拟议研究结果可能有助于改进当前的抗病毒策略，并将为CMV复制和同种异体排斥之间的关系提供新的知识。进行这项研究并完成职业发展活动将使这位候选人处于有利地位，建立一个独立的临床研究生涯，专注于应用病毒发病机制和抗病毒免疫方面的新发现，造福于免疫功能低下和健康的病毒感染儿童。相关性(见说明)：巨细胞病毒(CMV)是一种普遍存在的病毒感染，在健康人中没有症状，但在免疫功能低下的患者中会导致重大疾病，如新生儿(先天性CMV)和移植接受者。从这一建议中获得的关于肺移植患者对CMV的T细胞免疫的更多知识可能适用于其他人群(例如新生儿)，并可能对CMV疫苗的开发有用。(摘要结束)

DESCRIPTION (provided by applicant): Cytomegaloviurs (CMV) is a DNA virus in the family Herpesviridae. After primary infection, CMV becomes latent with potential for future reactivation ofthe latent virus. Cytomegalovirus (CMV) is the most important source of morbidity from an infectious pathogen following lung transplantation, causing deleterious direct effects (pneumonia) and indirect effects, such as enhanced rejection of the donor lung (allograft). The limiting factor in the long-term survival of lung transplantation patients is allograft rejection. Multiple studies have confirmed a strong association between CMV infection and rejection. CMV-specific T-cell responses are very important in controlling CMV replication, but very little investigation has been done in evaluating the role of CMV-specific T cell-mediated immunity in the context of rejection, particularly for lung allografts. The central objective of this proposal is to determine if the measurement of CMV-specific T cell responses in lung transplant patients can be used as a predictor of the risk of allograft rejection and poor control of CMV load. The aims of the study are: 1. Determine if circulating CMV-specific T-cell responses predict protection from lung allograft rejection in transplant recipients. 2. Determine the relationship of lung allograft rejection with subclinical CMV infection in the blood and lung. 3. Determine the role of CMV-specific T-cell responses in the lung for predicting protection from lung allograft rejection and decreased lung viral load. Results from the proposed studies of CMV-specific T-cell responses and viral load may allow improvement of current anti-viral strategies, and will provide new knowledge about the relationship between CMV replication and allograft rejection. Conducting this study and completing the career development activities will allow this candidate to be well-positioned to establish an independent clinical research career focusing on application of new discoveries in viral pathogenesis and anti-viral immunity to the benefit of immunocompromised and healthy children with viral infections. RELEVANCE (See instructions): Cytomegalovirus (CMV) is a ubiquitous viral infection, which is asymptomatic in healthy people but causes significant disease in immunocompromised patients, such as neonates (congenital CMV) and transplant recipients. Increased knowledge from this proposal about T-cell immunity to CMV in a lung transplant patient may be applicable to other populations (e.g. neonate) and may be useful for CMV vaccine development. (End of Abstract)