Grant: Operating Grant

Scleroderma is an incurable and potentially deadly disease characterized by blood vessel damage, inflammation and autoimmunity, resulting in excessive collagen deposition in skin and internal organs of patients. Therapeutic interventions tested in currently available preclinical animal models of Scleroderma do not translate well from the bench to clinic. An animal model that resembles the human disease is urgently needed. Patients with circulating anti-topoisomerase I autoantibodies (anti-Scl70 autoantibodies) have the poorest prognosis in terms of disease severity. High titers of antitopoisomerase I autoantibodies is an indication that the patient's immune system is attacking a selfprotein named DNA topoisomerase I. Therefore, we propose to use topoisomerase I and immune cells, such as dendritic cells, of mice to trigger scleroderma in mice. Our preliminary results have been promising since we have detected anti-topoisomerase I autoantibodies, vascular damage, inflammation and collagen deposition in both lungs and skin of these mice. Our mouse model of scleroderma will serve as a valuable tool to investigate the immune mechanisms that govern this complex disease and also to test novel therapies to prevent and even reverse scleroderma.