Immunopathogenesis, mechanisms of prevention and surrogate endpoints in NOD mice (Muir, Atkinson, She, Schatz):

The goal of this project is to improve our understanding of the immune defects that lead to type 1 diabetes, to study the molecular pathways leading to diabetes prevention and to identify surrogate endpoints that may be of value in upcoming immunotherapy trials. The genetic makeup of the NOD results in multiple immune defects, but the cause of the disease is not fully understood. Diabetes in NOD can be prevented by modulation of immunity using both antigen-specific (insulin B chain, glutamic acid decarboxylase [GAD]) and non-specific therapies (complete Freund’s adjuvant [CFA]). In this project, the immune function of NOD mice will be investigated by examining gene expression in immune cells that confer different susceptibilities to diabetes. T lymphocyte clones that are derived from the islets of NOD mice and are: 1) specific for either insulin B chain or GAD and 2) that either promote or inhibit diabetes will be subjected to microarray analysis in their basal and activated states. To ensure that changes in gene expression are relevant to the complex in vivo responses that cause diabetes, fresh mixed cell populations from draining lymph nodes and spleen, and populations enriched for lymphocyte subsets or antigen-presenting cells by negative immunomagnetic selection will also be examined in basal and stimulated states. Those genes that show consistent associations with protection from or aggravation of islet autoimmunity will be cloned and their function further investigated. We have demonstrated that the protective effect conferred to NOD mice by insulin B chain immunization does not occur in NOD.IL4-/- knockout mice. This is consistent with the hypothesis that TH2 immune responses against islet antigens are able to prevent harmful autoimmunity. We will take advantage of this experimental distinction to determine how gene expression in normally protective immune cell clones or populations is altered when the cells are placed in an IL-4 deficient environment and vice versa. We will also determine whether IL-10 influences expression of immunoregulatory genes using newly available NOD.IL10-/- knockout mice and NOD.IL4-/-IL1-/- double knockout mice. In our preliminary microarray studies, we have profiled gene expression in insulin B chain-treated mice (protected against diabetes) and insulin A chain-treated mice (controls). This ongoing study using NOD and NOD kockouts treated with multiple preventive agents should provide us with a powerful tool to better understand the immunopathogenesis, identify the common pathways leading to prevention and surrogate markers for prevention trials. Future studies will focus on characterizing the functions of the genes of interest and to perform translational studies in humans.
 

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