The proposed Denver Autoimmunity Center of Excellence combines the efforts of investigators with faculty appointments at the University of Colorado Health Sciences Center. Affiliated institutions include the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, the Children's Hospital of Denver, the University Hospital of Denver, the Rocky Mountain Multiple Sclerosis Center, as well as the Denver Arthritis Clinic. Faculty have been recruited from the Departments of Immunology, Pediatrics, Medicine, Neurology, Dermatology, Pathology, and Preventative Medicine/Epidemiology, and the Human Medical Genetics Program. Within the Departments of Pediatrics and Medicine, subspecialties include endocrinology, rheumatology, clinical immunology, nephrology, pulmonary and gastroenterology. There are unique resources for clinical investigation and strong basic faculty, and in many instances a track record for combining basic and clinical investigation. The proposed Autoimmunity Center includes a strong research and clinical base in type 1 diabetes, celiac disease, systemic lupus, rheumatoid arthritis, multiple sclerosis, autoimmune skin disease, autoimmune pulmonary diseases as well as other autoimmune disorders. One unique clinical resource involves ongoing studies of newborns from both the general population and relatives of patients with type 1 diabetes who are HLA typed using cord blood and then evaluated prospectively for the development of autoantibodies associated with type 1A diabetes and disease A major strength of the current proposal we believe sit he breadth of work in Denver studying T cell recognition and biology, genetics, and the biology of inflammatory and cytokine mediators. In the current proposal, two clinical trials are proposed. Clinical Project 1 will evaluate subcutaneous insulin vaccination to prevent the appearance of anti-islet autoantibodies in infants at high risk for the development of autoantibodies and disease. Clinical Project 2 will test humanized anti-C5 mAbs in patients with active lupus nephritis. The three proposed basic components are: 1) to define the T cell specificities and distribution of insulin- and islet antigen- reactive T cells in murine models and patients with type 1; diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine patients with type1 diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine production and disease in collagen- induced arthritis and rheumatoid synovium; and 3) to define the non- MHC genetic contributions to different clinical subtypes of autoimmune polyendocrine syndrome II. The three basic projects will provide important information to design future clinical trials , to monitor the effectiveness of immunologic therapies, and/or provide surrogate markers to correlate with immunologic therapies in autoimmune diseases.
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