Immune Mechanisms of Large-airway Lymphocytic Bronchitis

 描述(由申请人提供)： 这是为John Greenland博士申请职业发展奖(CDA-2)，John Greenland博士是旧金山退伍军人医疗服务中心肺和重症监护科的一名专职医生，他正在以患者为导向的肺移植免疫学研究中确立自己的研究员地位。CDA-2奖项将为格陵兰博士提供必要的支持，以实现以下目标：(1)提高对慢性肺排斥反应预测因素的了解，(2)获得生物信息学和高级T细胞免疫学方面的理论和实践技能，(3)为未来改善肺移植后监测的介入试验奠定机制基础，以及(4)建立专注于肺移植免疫学的独立临床研究事业。为了实现这些目标，格陵兰博士组建了一支指导团队，成员包括：(1)主要导师乔治·考伊博士，他是国际上受人尊敬的肺部免疫学权威，有指导翻译研究人员的记录；(2)大卫·戴克博士，公认的翻译T细胞免疫学家；(3)唐启智博士，人类移植免疫学专家；以及(4)杰弗里·戈登博士，他在肺移植临床研究方面拥有超过25年的经验。此外，他还将受益于尼克·朱厄尔博士、斯科特·博伊德博士和柯克·琼斯博士分别在生物统计学、生物信息学和病理学方面的指导和指导，以及刘易斯·拉尼尔博士和马克·安塞尔博士的研究支持。这项拟议的研究扩展了格陵兰博士最近发表的研究结果，即肺移植后监测活检中的淋巴细胞性支气管炎(LB)可以预测慢性排斥反应的发展，表现为闭塞性细支气管炎综合征(BOS)。这项拟议的研究将建立一个预期的肺移植受者队列，以实现以下特定目标：(1)确定淋巴组织中浸润性T细胞的表型和特异性， (2)评估LB期间的调节性、体液和先天淋巴细胞反应，以及(3)前瞻性地评估LB作为BOS的预测因子。这些研究将利用下一代流式细胞术和测序技术来表征接受移植后支气管镜检查的患者的外周血液、呼吸道刷检和活检以及支气管肺泡灌洗液中的免疫反应。对LB的更好理解可能会使其成为BOS发生的重要生物标志物，而在肺移植后供体特异性免疫反应的背景下理解LB将为优化免疫抑制和诱导耐受提供新的工具。

 DESCRIPTION (provided by applicant): This is an application for a Career Development Award (CDA-2) for Dr. John Greenland, a staff physician in the Pulmonary and Critical Care Section of the San Francisco VA Medical Service who is establishing himself as an investigator in patient-oriented research into the immunology of lung transplantation. This CDA-2 award will provide Dr. Greenland with the necessary support to accomplish the following goals: (1) to improve the understanding of predictors of chronic lung rejection, (2) to acquire theoretical and practical skills in bioinformatics and advanced T cell immunology, (3) to establish the mechanistic foundations for future interventional trials to improve post-lung transplant surveillance, and (4) to establish an independent clinical research career focused on lung transplantation immunology. To achieve these goals, Dr. Greenland has assembled a mentoring team consisting of (1) primary mentor Dr. George Caughey, an internationally respected authority in pulmonary immunology with a track record of mentoring translational researchers, (2) Dr. David Daikh, a recognized translational T cell immunologist, (3) Dr. Qizhi Tang, an expert in human transplant immunology; and (4) Dr. Jeffrey Golden, who has over 25 years of experience with clinical research in lung transplantation. Additionally, he will benefit from tutorials and mentorship from Drs. Nick Jewell, Scott Boyd, and Kirk Jones, in biostatistics, bioinformatics, and pathology, respectively; and research support from Drs. Lewis Lanier and Mark Ansel. The proposed research expands on Dr. Greenland's recently published findings that lymphocytic bronchitis (LB) on post-lung transplant surveillance biopsy predicts the development of chronic rejection in the form of bronchiolitis obliterans syndrome (BOS). The proposed study will establish a prospective cohort of lung transplant recipients to achieve the following specific aims: (1) determine the phenotype and specificity of infiltrating T cells in LB, (2) assess regulatory, humoral, and innate lymphocyte responses during LB, and (3) prospectively assess LB as a predictor of BOS. These studies will make use of next-generation flow cytometry and sequencing techniques to characterize immune responses in peripheral blood, airway brushings and biopsies, and bronchoalveolar lavage fluid from patients undergoing post-transplant surveillance bronchoscopy. A better understanding of LB may allow it to become an important biomarker for the development of BOS, while understanding LB in the context of the post-lung transplantation donor-specific immune response will lead to new tools for optimizing immunosuppression and inducing tolerance.