Using high T-bet-expressing cells and Serum Chemokines as Indicators of Disease Severity in Sarcoidosis

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PROJECT SUMMARY/ABSTRACT Sarcoidosis is a systemic granulomatous disease of unknown etiology that affects multiple organs, especially the lungs. It has a wide range of clinical outcomes, including progressive lung disease and multi-organ involvement. Due to the lack of reliable or validated markers for these outcomes, sarcoidosis presents many challenges to clinicians, especially in light of the toxicities from immunosuppressive therapies used as treatment. My goal for this K23 award is to determine how specific immune cells and proteins relate to systemic organ burden and pulmonary function in sarcoidosis patients. While accomplishing this goal, I will pursue a rigorous career development plan to expand my skills in clinical research methods and T cell biology. The blood markers I will study are biologically linked to IFN-γ, an essential cytokine in sarcoidosis inflammation. These markers include: 1) a specific subset of T helper cells that can produce high amounts of IFN-γ and 2) serum levels of chemokines induced by IFN-γ that traffic immune cells to inflamed tissues. I have generated preliminary data for these markers using a well-phenotyped longitudinal sarcoidosis cohort established by my primary mentor, Dr. Laura Koth. The T cell population of interest is defined by production of the transcription factor T-bet, which regulates IFN-γ production. Using multi-parameter flow cytometry, I identified a population of T helper cells that have distinctly high levels of T-bet protein (T-betHi cells). These T-betHi cells were present almost exclusively in subjects with pulmonary function test (PFT) declines. Initial in vitro assays of these cells suggest that they have exceptionally high capacity to produce IFN-γ. Aim 1 will determine how IFN-γ production in these T-betHi cells relates to their potential pathogenicity. The second group of markers includes three IFN-γ-induced chemokines (CXCL9, CXCL10, and CXCL11), which were the subject of two of my recent publications. I showed that serum levels of these chemokines had distinct associations with the longitudinal pulmonary function changes and organ involvement. These associations may be due to their underlying biology and therefore carry specific relevance in the disease. Thus, in Aims 2 and 3, I will determine the relationship of both T-betHi cells and these chemokines to outcomes in two sarcoidosis cohorts. I have been helping Dr. Koth enroll subjects into these cohorts and I run study visits to collect the clinical data I will use in this proposal. These cohorts include subjects with newly diagnosed disease who have repeated follow-up over up to two years. I will determine how these markers relate longitudinally to the number of organs affected (Aim 2) and pulmonary function (Aim 3). In addition to offering direct involvement with these cohorts, Dr. Koth, will share her lab space and provide support to measure these blood markers. I will also benefit from the clinical research and biostatistical and expertise of my co-mentors, Drs. Woodruff and Allen. As part of my training plan, I will supplement skills I have acquired during my Master's in Clinical Research through additional epidemiology and statistics coursework. During this award I will generate data to apply for R01 funding to become an independently funded clinical and translational researcher.