Despite advances in the ability to predict future cases of type 1 diabetes and attempts to intervene/interrupt the progression towards overt disease, major voids remain in our understanding of the autoimmune mechanisms that underlie beta cell destruction and the interplay between immunological and genetic factors that contribute to disease progression. The overall objective of this project is to delineate the immunologic mechanisms underlying the formation of type 1 diabetes through investigation of populations with-or at various levels of risk for the disease; studies that are crucial to properly addressing the aforementioned knowledge voids. A key facet to meeting this objective will involve investigation of persons at the extreme ends of the prediabetic period (i.e., low- to high-risk newborns and persons at the latter stages of autoimmune disease participating in disease prevention trials). Hence, we will perform assessments on persons participating in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet, as well as subjects from our PANDA (Prospective Assessment of Newborns for Diabetes Autoimmunity) study. This proposal will test two hypotheses: 1) that CD1d-restricted NK T cells interact with dendritic cells and that this axis is dysfunctional in at-risk pre-diabetic individuals, and 2) that the development of disease correlates with parameters of T cell autoimmunity wherein T helper-1 (Th1)-like immunities against an expanded repertoire of beta cell antigens (afforded in-part by the aforementioned dysfunctions) occurs in association with diminished Th2-like responses. These hypotheses will be tested through performance of four specific aims including: 1) monitoring T cell responses (blastogenesis, cytokine production) to islet cell antigens including insulin, 2) analysis of dendritic cell subsets and antigen presenting cell function, 3) determining the frequency of circulating CD1d-restricted T cells, and 4) analysis of the effector functions of CD1d-restricted T cell clones. Irrespective of whether we prove or disprove these hypotheses, we will establish parameters of the cellular immune response that are fundamental for the interpretation of autoimmunity in type 1 diabetes and their linkages with risk for the disease.
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