This proposal rests upon the hypothesis that mycobacterial induction of CD4+ T cell energy leads to loss of sarcoidosis pulmonary function. Use of antimycobacterial therapy normalizes expression of key mediators of CD4+ T cell function, such as p56Lck, leading to increased IL-2 and IFN? production, and restoration of lung function. The transformative nature of this proposal is that it allows us to translate molecular mechanisms identified at the bench to immune function within the host, and ultimately to a clinical endpoint associated with sarcoidosis mortality, absolute FVC. Phase I analysis of the eight subjects completing the CLEAR regimen revealed an increase in the absolute FVC of 0.42 liters, reflecting a mean increase in absolute FVC of 16% from baseline. The observed pulmonary improvement was accompanied by an increase in functional capacity and perception of dyspnea that exceeds current sarcoidosis therapeutic options, such as steroids and infliximab. These encouraging efficacy data has led us propose a multicenter, randomized, double-blind, placebo-controlled Phase II investigation of the effects of CLEAR regimen on subjects with chronic, active pulmonary sarcoidosis. Subjects will be required to have systemic responses to ESAT-6 for study entry. The primary endpoint will be change in absolute FVC. Secondary endpoints will include investigation of steroid-sparing effects of CLEAR regimen, assessments of 6MWD, SGRQ, chest tomography (CT) radiographic changes and effects on T cell biologic function through the induction of IL-2 pathway in sarcoidosis BAL and PBMC. In addition, we will use reporter mycophages to characterize viable mycobacteria within sarcoidosis BAL. The safety profile will be assessed through detection of adverse events and abnormal lab values. The 1o and 2o endpoints will be obtained over a six month interval, laying the foundation for a definitive Phase 3 investigation.
Sarcoidosis is a granulomatous disease of unknown etiology, whose association with mycobacteria continues to strengthen. Phase I analysis of antimycobacterial therapy reveals improvement in forced vital capacity, six minute walk distance, and quality of life assessments among sarcoidosis subjects who complete this regimen. This Phase II proposal involves testing a larger cohort of patients, as well as defining the immunologic basis for the improvement. (End of Abstract)
| Morrison, Robert J; Katsantonis, Nicolas-George; Motz, Kevin M et al. (2018) Pathologic Fibroblasts in Idiopathic Subglottic Stenosis Amplify Local Inflammatory Signals. Otolaryngol Head Neck Surg :194599818803584 |
| Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10: |
| Celada, Lindsay J; Rotsinger, Joseph E; Young, Anjuli et al. (2017) Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4+ T Cell Proliferation. Am J Respir Cell Mol Biol 56:74-82 |
| Chioma, Ozioma S; Drake, Wonder P (2017) Role of Microbial Agents in Pulmonary Fibrosis?. Yale J Biol Med 90:219-227 |
| Hawkins, Charlene; Shaginurova, Guzel; Shelton, D Auriel et al. (2017) Local and Systemic CD4+ T Cell Exhaustion Reverses with Clinical Resolution of Pulmonary Sarcoidosis. J Immunol Res 2017:3642832 |
| Rotsinger, Joseph E; Celada, Lindsay J; Polosukhin, Vasiliy V et al. (2016) Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets. Am J Respir Cell Mol Biol 55:128-34 |
| Celada, Lindsay J; Hawkins, Charlene; Drake, Wonder P (2015) The Etiologic Role of Infectious Antigens in Sarcoidosis Pathogenesis. Clin Chest Med 36:561-8 |
| Richmond, Bradley W; Richter, Kyra; King, Lloyd E et al. (2014) Resolution of chronic ocular sarcoidosis with antimycobacterial therapy. Case Rep Intern Med 1: |
