Neuropeptides as Mediators of Th2-type Immunity

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DESCRIPTION (provided by applicant): Bi-directional communications between the CNS and the immune system are mediated through common ligands and receptors, i.e. cytokines, hormones, and neuropeptides. There is ample evidence that the neuropeptides VlP and PACAP affect innate immunity through their effect on macrophages. However, the role of VlP/PACAP in the maturation and activity of dendritic cells (DC) and microglia, major participants in innate immunity and antigen presentation in the periphery and CNS, is not known. Although DCs and microglia are essential for pathogen elimination, unrestrained activation leads to tissue destruction. There are numerous examples of DCs involvement in autoimmune diseases, such as SLE, RA, MS, insulin-deficient diabetes. DCs and microglia stimulate and reactivate T cells, and promote the generation and accumulation of pro-inflammatory Th1 effectors. Endogenous agents such as anti-inflammatory cytokines, glucocorticoids, prostaglandins, limit the immune response by deactivating the antigen presenting cells, and promoting Th2 immunity. The central hypothesis in this proposal is that VlP and PACAP inhibit the innate immune response of DCs and microglia, preventing pro-inflammatory cytokine and chemokine (CK) production, reduce their capacity to activate T cells, and bias effector T cells towards Th2 responses. Specific Aim I is focused on the effects of VlP/PACAP on DCs, including production of specific cytokines and CK, expression of CK receptors and directed migration of DCs, expression of stimulatory/costimulatory molecules and T cell activation. Specific Aim II addresses similar questions in two models of microglial activation, LPS stimulation that induces primarily an innate immune response, and GM-CSF treatment resulting in DC-resembling microglia. In Specific Aim Ill we evaluate VlP/PACAP as agents that induce DCs and microglia to promote the Th2 effector accumulation and response. These studies will contribute to a better understanding of the physiological relevance of neuropeptides, particularly in establishing and maintaining immune deviation, and to the future development of appropriate receptor agonists with the capacity to limit innate inflammatory responses, and to reverse the predominant Th1 response in autoimmune diseases in the periphery and the CNS.