Immune Mechanisms of Large-airway Lymphocytic Bronchitis

大气道淋巴细胞性支气管炎的免疫机制

• 批准号: 9474093
• 负责人: JOHN GREENLAND
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9474093
• 关键词: Acute; Affect; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Award; Bioinformatics; Biometry; Biopsy; Bronchiolitis Obliterans; Bronchitis; Bronchoalveolar Lavage Fluid; Bronchoscopy; Caregivers; Caring; Cell Count; Cells; Characteristics; Chronic; Clinical Research; Clone Cells; Critical Care; Detection; Development; Early Diagnosis; Epithelial; Epithelial Cells; FOXP3 gene; Flow Cytometry; Foundations; Frequencies; Future; Goals; Greenland; Health; Helper-Inducer T-Lymphocyte; Human; IL2RA gene; Immune; Immune response; Immune system; Immunologist; Immunology; Immunophenotyping; Immunosuppression; Improve Access; International; Intervention; Intervention Trial; K-Series Research Career Programs; Lead; Lesion; Light; Liquid substance; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Lymphocytosis; Medical; Mentors; Mentorship; Methods; Natural Killer Cells; Pathologic; Pathology; Patients; Performance; Phenotype; Physicians; Population; Production; Prospective cohort; Publishing; Regulatory T-Lymphocyte; Research; Research Personnel; Research Support; San Francisco; Services; Severities; Specificity; Syndrome; T cell response; T-Lymphocyte; Techniques; Testing; Time; Transplant Recipients; Transplantation; Transplantation Immunology; Validation; Veterans; arm; authority; base; biomarker development; career; cell type; chemokine receptor; cohort; cytokine; cytotoxic; deep sequencing; experience; improved; isoimmunity; next generation; patient oriented research; peripheral blood; predicting response; prevent; programs; prospective; public health relevance; receptor expression; response; skills; tool; transcription factor; translational scientist

 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.

 描述（由申请人提供）： 这是约翰·格林兰 (John Greenland) 博士的职业发展奖 (CDA-2) 申请，他是旧金山退伍军人医疗服务中心肺科和重症监护科的一名主治医师，他本人正在以患者为导向的研究领域担任调查员。该 CDA-2 奖项将为 Greenland 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素的理解，(2) 获得相关理论和实践技能。生物信息学和高级T 细胞免疫学，(3) 为未来的介入试验奠定机制基础，以改善肺移植后监测，(4) 建立专注于肺移植免疫学的独立临床研究事业。组建了一个指导团队，成员包括 (1) 首席导师 George Caughey 博士，一位国际知名的肺免疫学权威，拥有指导转化研究人员的记录，(2) David Daikh 博士，一位公认的转化 T 细胞免疫学家，(3) Qizhi Tang 博士，人类移植免疫学专家；(4) Jeffrey Golden 博士，拥有超过 25 年的肺移植临床研究经验。斯科特·博伊德（Scott Boyd）和柯克·琼斯（Kirk Jones）分别在生物统计学、生物信息学和病理学领域；以及刘易斯·拉尼尔（Lewis Lanier）博士和马克·安塞尔（Mark Ansel）博士的研究扩展。肺移植后监测活检中发现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生。拟议的研究将建立肺移植受者的前瞻性队列，以实现以下具体目标：（1） ) 确定 LB 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外周血中的免疫反应。气道刷检和活检，以及接受移植后监测支气管镜检查的患者的支气管肺泡灌洗液，在了解 LB 的同时，更好地了解 LB 可能使其成为 BOS 发展的重要生物标志物。在肺移植后供体特异性免疫反应的背景下，将产生优化免疫抑制和诱导耐受的新工具。