T cells express receptors for endogenous neuroactive molecules such as opioids, substance P, and somatostatin which can modulate T cell responses. Gamma-amino butyric acid (GABA) is the major inhibitory neuro-transmitter in the central nervous system. The investigators' preliminary studies have demonstrated that T cells express functional GABA-A receptors. Activation of these GABA-A receptors inhibited T cell proliferation and IL-2 production. Moreover, administration of GABA in vivo inhibited the adoptive transfer of insulin-dependent diabetes mellitus (IDDM) to non obese diabetic (NOD) mice. These preliminary findings suggest that lymphocytic GABA receptors can down-regulate inflammatory processes. This proposal will test the hypothesis that like their neuronal counterparts, lymphocytic GABA receptors are 1) comprised of subunits which are differentially expressed on different T cell populations during development, and that 2) their expression can be regulated by several factors including the activation of T cells, ligands for GABA-A receptors, cytokines, and insulin. The applicant will also test the hypothesis that activation of lymphocytic GABA-A receptors can modulate T cell function, including their cytokine and surface molecule expression, and cytotoxicity. The applicant will characterize the mechanism(s) by which GABA mediated its immuno-modulatory action on T cells. Finally, since GABA inhibited T cell proliferation in vitro and the adoptive transfer of diabetes in vivo , they hypothesize that GABA will inhibit antigen-specific delayed type hypersensitivity (DTH) responses, as well as the spontaneous development of diabetes in NOD mice in vivo. Demonstrating that GABA inhibits Th1-mediated inflammatory responses in vivo could lead to novel approaches for inhibiting T cell-mediated inflammatory process and autoimmune disease. Thus, the results of this proposal will provide basic insights into a new mode of neuro-immunological regulation of T-cells and inflammatory responses. Moreover, the results may have potential clinical application for down-regulating inflammatory processes in man.
