Impact of CCR5 inhibition on Sarcoid Immunophenotypes

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DESCRIPTION (provided by applicant): Sarcoidosis is a chronic multi-system disease of unknown etiology characterized by formation of noncaseating granulomatous infiltrates, most often within the lungs. While the specific causality of sarcoidosis is enigmatic, the granuloma formation and other pathologic findings of this disorder almost certainly reflect a dysregulated immune response to an unidentified antigen among genetically predisposed individuals. The primary hypothesis of this proposal is that systematic collection (Specific Aim 1) and multidisciplinary study of clinical specimens from sarcoidosis patients (Specific Aim 2) will result in new insights into the etiopathogenesis of this disease and identification of prognostic biomarkers. In addition, we also hypothesize that CCRS antagonism in sarcoidosis patients with maraviroc will safely diminish the intrapulmonary immigration and sequestration of monocytes and T-cells, decrease activation and differentiation of these cells, and result in measurable Improvements of abnormal, clinically-relevant inflammatory parameters (Specific Aim 3). The specific aims of this proposal are 1) To collect residual lymph node specimens (mediastinoscopy and endobronchial ultrasound guided fine needle aspirations [EBUS-FNA]), bronchoalveolar lavage fluid (BALF), skin biopsies, and peripheral blood of sarcoidosis subjects, along with detailed subject clinical data (e.g., demographics, disease phenyotyping) for provision to the collaborative Genomic and Informatics Center (GIC); 2) To analyze portions/aliquots of the specimens collected in Aim 1 In immunobiological phenotyping assays. These studies will include measures of protein and.gene expressions related to CD4 T-cell activation and differentiation (using flow cytometry and RT-PCR, respectively) that we have discovered are highly associated with the prognosis of other chronic immunological lung diseases; and 3) To determine effects of CCR5 inhibition on key trafficking, activation, and effector functions of CD4 T-cells and monocytes/macrophages of sarcoidosis patients. The resultant data will shape the design of more definitive clinical trials i sarcoidosis patients to follow, and will provide insight on potential therapeutic uses of CCR5 inhibitors in sarcodosis.