Bidirectional communication between the immune system and the nervous system was originally hypothesized on the basis of defined lesions in the brain which affected immune responses. More recent investigations have begun to delineate the biochemical and neurologic pathways which constitute this neuroimmune axis. Neuropeptides have been shown to modulate the function of diverse immune effector cells and in turn, lymphokines appear to interact with specific central nervous system neurons involved in the neuroimmune axis. Neuromodulation of the immune response is effected by interaction of neuropeptides with specific, high affinity receptors on immune effector cells. Vasoactive intestinal peptide (VIP) is a 28 amino acid neuromodulator found in high concentrations in both central and peripheral nervous tissue; peptidergic fibers release VIP in nerve endings which surround immune effector cells in both thymus and gut associated lymphoid tissue. Specific, high affinity receptors for VIP have been identified on both normal and leukemic human lymphocytes. This proposal will seek to purify and characterize the VIP receptor on human lymphocytes, clone the VIP receptor cDNA, and compare its structure with VIP receptors in central nervous tissue. Further experiments will utilize monoclonal antibodies directed against receptor epitopes to delineate which subpopulations of immune effector cells possess this neuropeptide receptor and to which anatomical immune tissue receptor positive cells preferentially migrate. Functional studies will then define whether VIP modulation of immunoglobulin production and natural killer (NK) cell activity is a direct effect on B cells and NK cells or is mediated via regulation of lymphokine production by T lymphocytes. Additional experiments are designed to investigate whether VIP modulates either proliferation of differentiation of leukemic cells. The molecular basis for VIP modulation of the immune response will be probed with experiments to compare expression of the VIP receptor gene in normal and leukemic lymphocytes and with studies designed to delineate the nature and function of lymphocyte proteins phosphorylated in the presence of VIP. These studies will contribute to a greater understanding of neuromodulation of the immune response with clinical relevance to the development of neuropeptide therapies for the treatment of both congenital and acquired immune deficiences.
