Deciphering the Relevance and Etiology of Th2 Cytokine Skewing in WASP KO Mice

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DESCRIPTION (provided by applicant): The precise pathogenesis of inflammatory bowel disease (IBD) is unknown, but data from animal studies suggest a dysregulated immune response to intestinal flora. We aim to aid in the understanding of this human disease by closely examining the pathogenesis of a novel animal model of IBD, Wiskott-Aldrich Syndrome Protein (WASP) knockout (KO) mice. WASP, identified as the protein defective in patients with Wiskott-Aldrich Syndrome (WAS), is an intracellular signaling molecule expressed exclusively in hematopoietic cells and involved in actin cytoskeletal rearrangements. WASP KO mouse T cells, similar to T cells from WAS patients, harbor severe T cell signaling defects. In addition, WASP KO mice develop colitis, similar to 10% of WAS patients who suffer from an IBD-like disease. Preliminary studies have shown an infiltration of lymphocytes, macrophages, and dendritic cells into the lamina propria of the inflamed WASP KO mouse colons. This lamina propria infiltrate produces elevated levels of the Th2 cytokines IL-4 and IL-13. In this proposal, we aim to define the roles of Th1 and Th2 cytokines in the development of colitis in WASP KO mice. We will investigate the immediate cellular source of Th2 cytokines and the proximal aberrant cell population that eventual leads to Th2 cytokine induction. Lastly, we will investigate the molecular mechanisms underlying Th2 cytokine skewing by examining the expression of transcription factors known to be critical in T cell and NK-T cell differentiation. Determining the cell types and mechanisms underlying Th2 cytokine skewing may aid in our understanding of the pathogenesis of IBD and lead to new therapeutic targets of the disease. In summary, we will study mice lacking the Wiskott-Aldrich Syndrome protein, a molecule missing in patients with Wiskott-Aldrich Syndrome, as a new model of inflammatory bowel disease. Determining the mechanisms underlying disease pathogenesis in these mice, which models a human disease also associated with intestinal inflammation, will aid in our understanding of the abnormalities that cause inflammatory bowel disease in humans and will hopefully lead to new treatment ideas for the disease.