IMMUNOPATHOGENESIS OF DIABETES--STUDIES IN INFANTS

DESCRIPTION (adapted from applicant's abstract): Genetic, immunological, and exogenous factors interact to induce pancreatic beta-cells autoimmunity in a small minority of the individuals who have a genetic predisposition to developing IDDM. Previous studies have proven that preclinical IDDM can be identified in children and adults with immune and metabolic markers. It has been demonstrated that persistent production of autoantibodies against (beta)- cell antigens in high-risk individuals almost always commenced prior to the time of study enrollment. It led into the hypothesis that the initiation of the autoimmune cascade and the resultant molecular and cellular changes that culminate in clinical disease, occur in the very early years of life. Because it identifies babies at high-risk for (beta)-cell autoimmunity prior to their earliest production of autoantibodies, the neonatal genetic screening program provides investigator the first chance ever to test the hypothesis in a cohort design. The following specific aims are proposed: (1) to identify newborn babies at increased risk for the development of IDDM from 3,000 (per year) at low risk in the general population and at higher risk among relatives of IDDM patients. Risk assessment using HLA and family history of diabetes will assign babies to five risk groups for the development of IDDM and autoantibodies: very high, high, moderate and low risk and protective groups. To improve participation and retention rates for the study, the psychological impact of diabetes screening on family members and the effects of exogenous factors (viruses, diet, etc.) that may trigger or modify the autoimmune process will be studied; (2) to determine the precise timing and sequence of the appearance of autoantibodies, GAD, IAA, ICA, IA2(beta) at 6, 12, and 18 months and then at one year intervals for all high/moderate risk subjects and a sample of low risk controls will be tested; (3) to study the interaction of antigen presenting cells, T cells and susceptibility genes in the Immunopathogenesis of diabetes, the expression levels of macrophage-derived PGS2 and Th1/Th2- associated cytokines (IL-4 and IFN-gamma) in longitudinal samples from high and low-risk subjects will be determined. Principle investigator will also determine whether endogenous retrovirus RNA expression in peripheral blood is altered in subjects who develop (beta)-cell autoimmunity; and (4) to identify specific molecular changes associated with disease progression by quantitative analyses of gene expression using DNAchips and microarray technologies. The most promising candidate genes will be further characterized in longitudinal samples using other techniques more suitable for large-scale studies. Since new program will explore a previously inaccessible preclinical phase of IDDM, the present studies should provide novel insights that may advance new genetic and immunologic technologies for predicting and preventing the disease.