Immune Mechanisms of Large-airway Lymphocytic Bronchitis

 描述（由申请人提供）： 这是约翰·格陵兰（John Greenland）博士的职业发展奖（CDA-2）申请，他是弗朗西斯科退伍军人管理局医疗服务中心肺部和重症监护科的一名主治医师，正在成为以患者为导向的免疫学研究的研究员。肺移植。该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）提高对慢性肺排斥预测因子的理解，（2）获得生物信息学和先进T细胞免疫学的理论和实践技能，（3）为未来的干预性试验建立机制基础，以改善肺移植后的监测，（4）建立以肺移植免疫学为中心的独立的临床研究事业。为了实现这些目标，Greenland博士组建了一个指导团队，包括（1）主要导师乔治Caughey博士，他是国际上受人尊敬的肺免疫学权威，有指导转化研究人员的记录，（2）大卫戴克博士，公认的转化T细胞免疫学家，（3）唐启智博士，人类移植免疫学专家;和（4）Jeffrey Golden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辅导和指导;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Greenland博士最近发表的研究结果，即肺移植后监测活检的淋巴细胞性支气管炎（LB）可预测闭塞性细支气管炎综合征（BOS）形式的慢性排斥反应的发展。该研究将建立一个前瞻性的肺移植受者队列，以实现以下具体目标：（1）确定LB中浸润T细胞的表型和特异性， (2)评估LB期间的调节性、体液性和先天性淋巴细胞反应，和（3）前瞻性评估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监测支气管镜检查的患者的外周血、气道刷检和活检以及支气管肺泡灌洗液中的免疫反应。更好地了解LB可能使其成为BOS发展的重要生物标志物，而在肺移植后供体特异性免疫应答的背景下了解LB将导致优化免疫抑制和诱导耐受的新工具。

 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.