The primary objective of this career development award is to acquire the skills and expertise to become an independent investigator in the field of rheumatic diseases. This will occur through a period of intense didactic and research training in the Division of Rheumatology at the Johns Hopkins University. This proposal will investigate the value of quantifying effector T cell polarization (type 1/type 2) and autoantigen- topoisomerase-1 (topo-1)-specific T cells as measures of lung disease activity and predictors of clinical outcomes in a large prospective cohort of scleroderma (SSc) patients. Lung involvement is currently the leading cause of morbidity and mortality in SSc patients. Interstitial lung disease (ILD) is the most common pulmonary manifestation. Experimental and clinical studies suggest that pulmonary fibrosis in SSc may result from a pro-fibrotic Th2/Tc2 polarized immune response and that an antigen-driven T cell activation is involved. To date, no single test reliably predicts progression towards lung fibrosis. Our preliminary studies suggest that Th2/Tc2 polarization of circulating T cells is strikingly associated with presence of ILD and that topo-1-specific CD8+ T cells are expanded in the lungs of patients with active alveolitis. We hypothesize that (i) the evolution of T cell responses towards a Th2/Tc2 phenotype is critical for the development of lung fibrosis and may be an early marker for SSc-ILD;(ii)the Th2/Tc2 pro-fibrotic T cell population is expanded in the lungs of patients with active ILD, quantitatively predicting rate and severity of disease progression;(Hi) amplification of the topo-1-specific T cell response during active ILD is quantitatively correlated with disease activity and predict clinical outcomes.
Aim #1 will study the evolution of T cell polarization and its relevance to the development of ILD in a large prospective cohort of well-defined SSc patients. The Johns Hopkins Scleroderma Center will provide dedicated clinical and research support for the entire duration of the project.
Specific Aim #2 will determine whether T cells with Th2/Tc2 polarized phenotype are enriched in the lungs of patients with active ILD and play a role in the pathogenesis of lung fibrosis. Th2/Tc2 T cell polarization will be measured in the blood and BAL fluid of the cohort patients (Aim1) undergoing bronchoscopy for suspected active ILD and correlated with the subsequent course of lung disease and outcome.
Specific Aim #3 will define if topo-1-specific T cells quantification in the blood and BAL of SSc patients with active ILD can accurately measure activity and predict disease outcomes. Relevance: The goal of this project is to determine whether a direct link exists between the magnitude and features of the immune response in SSc patients and the development of specific clinical phenotypes such as lung fibrosis. This may allow the identification of more reliable markers for disease activity, of better predictors of outcome and potentially of novel SSc-specific therapeutic targets.
|Cottrell, Tricia R; Wise, Robert A; Wigley, Fredrick M et al. (2014) The degree of skin involvement identifies distinct lung disease outcomes and survival in systemic sclerosis. Ann Rheum Dis 73:1060-6|
|Fava, Andrea; Wung, Peter K; Wigley, Fredrick M et al. (2012) Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud's phenomenon. Arthritis Care Res (Hoboken) 64:925-9|
|Le, Elizabeth N; Wigley, Fredrick M; Shah, Ami A et al. (2011) Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis 70:1104-7|
|Grader-Beck, Thomas; Boin, Francesco; von Gunten, Stephan et al. (2011) Antibodies recognising sulfated carbohydrates are prevalent in systemic sclerosis and associated with pulmonary vascular disease. Ann Rheum Dis 70:2218-24|
|Manno, Rebecca; Boin, Francesco (2010) Immunotherapy of systemic sclerosis. Immunotherapy 2:863-78|
|Boin, Francesco; Franchini, Stefano; Colantuoni, Elizabeth et al. (2009) Independent association of anti-beta(2)-glycoprotein I antibodies with macrovascular disease and mortality in scleroderma patients. Arthritis Rheum 60:2480-9|