This proposed competitive renewal of a Cooperative Study Group for Autoimmune Disease Prevention combines the efforts of investigators with faculty appointments at the University of Colorado Denver Health Sciences Center (UCDHSC), in Denver, Colorado and the Benaroya Research Institute in Seattle, Washington. Affiliated institutions at the UCDHSC include the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, and the University Hospital of Denver. A major resource and emphasis for the proposed studies relate to studies of human immunology in the context of prospective analysis of well defined populations, in part derived and related to our more than a decade of experience with the DAISY study of type 1 diabetes autoimmunity. Three Projects are proposed. Project by Holers: Rheumatoid Arthritis: Biomarkers of Progression from autoimmunity to disease which builds on prospective identification of 'asymptomatic' individuals expressing rheumatoid arthritis autoimmune markers made possible by the initial Autoimmune Prevention Center grant. Project by Eisenbarth: Type 1A Diabetes: Expanding the Limits of Genetic Prediction which will create and study the largest group of twins of patients with type 1 diabetes comparing and contrating to similarly characterized sibling groups, some of which at birth have a risk of islet autoimmunity approaching 80%; and Project by Nepom: Checkpoints and autoimmune homeostasis in T1D. Two Pilot studies are also proposed, 1) Preclinical Pulmonary Disease in Systemic Autoimmunity, and 2) TSLP (Thymic Stromal Lymphopoetin) in T Cell 'mediated' pulmonary disease. Investigators at the Benaroya and the Barbara Davis Center/UCDHSC have a long history of collaborative efforts and complementary expertise in the field of the immunology of autoimmunity including Dr. Eisenbarth's sabbatical at the Benaroya, combined design and now Trialnet initiation of clinical studies for prevention of immune mediated beta cell destruction (Gottlieb and Greenbaum), multiple collaborative studies during the initial Aut Prev Ctr grant, including joint studies of rheumatoid arthritis and type 1 diabetes. In addition, we welcome the opportunity to collaborate with the proposed Cooperative Study group for Autoimmune Disease Prevention. During the current grant our joint Center has initiated DAISY like prospective studies of rheumatoid arthritis, initiated a program to obtain pancreas from islet autoantibody cadaveric donors (a program planned to be international JDRF/NIH effort), defined a series of tetramer epitopes in type 1 diabetes and regulation of expression or tetramer positive T cells, discovered a remarkable risk of activating 'infantile' islet autoimmunity based upon synergy of specific high risk alleles (DR3/4-DQ8) and haplotype sharing with siblings, and defined related but unique risk factors for celiac disease. Faculty for the Cooperative Study Group has been recruited from the Departments of Immunology, Pediatrics, Medicine, and Preventive Medicine/Epidemiology, and the Human Medical Genetics Program. Within the Departments of Pediatrics and Medicine, subspecialties include endocrinology, rheumatology, clinical immunology, nephrology, and pulmonary. There are unique resources for clinical investigation and strong basic science faculty and in many instances a track record for combining basic and clinical investigation.
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