Tolerance is an essential component for the regulation of the immune response. The state of tolerance reflects complex interactions amongst distinct cells and it is tailored to very specific challenges in different stages of development. In the digestive tract, the host must not overreact to the dietary and microbial antigens in the lumen. Several Th cell responses collaborate to limit immune reactivity through multiple mechanisms. Crohn's disease and ulcerative colitis are chronic, relapsing inflammatory diseases whose exact pathogenesis and etiology remain unknown. Recent studies in immunology, microbiology and cell biology suggest that IBD results from a dysregulated immune response to enteric antigens in genetically susceptible hosts. The importance of appropriate immune responses to enteric flora is illustrated in mouse models where Helicobacter hepaticus can induce regulatory Th cells in normal mice while exacerbating intestinal inflammation in immunodeficient animals. Adenosine is released from inflamed or hypoxic tissues and mediates many physiological responses. Studies suggest that adenosine is a naturally occurring autocoid that limits tissue damage associated with inflammation. The effects of adenosine are controlled by four receptors (A1, A2A, A2B, and A3), which are variably expressed on immune cells depending on cell type and species. Activation of A2A adenosine receptors (A2AAR) on immune cells produces a series of responses that in general can be categorized as anti-inflammatory. In models of injury where the damage is mediated by Th cells, A2AAR agonists protect the host by inhibiting pathogenic Th cells. The hypothesis for this application is that agonists of A2AAR favor the development of cells with a regulatory Th cell phenotype especially during the early post-weaning stage of immune cell maturation. This hypothesis will be tested in the following Specific Aims:
Aim 1. Examine the role of the A2A adenosine receptor in regulatory T cell development.
Aim 2. Evaluate Th cell differenitation by antigen presenting exposed to A2A receptor agonists. This proposal will explore A2AAR agonists as novel immunotherapies for tolerance induction in mucosal tissues. Characterization of the mechanisms by which these compounds control Th cell function will provide new insights that can guide the development of their use for the prevention or treatment of IBD and possibly other diseases that are controlled by regulatory T cells. ? ? ?
