Immune Mechanisms of Large-airway Lymphocytic Bronchitis

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 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.