A novel mechanism for immunosuppression: from neuropeptides to regulatory T cells.

Vasoactive intestinal peptide (VIP), a well-known immunoregulatory neuropeptide, affects both innate and adaptive immunity, and acts as a major anti-inflammatory factor in animal models of autoimmune diseases. VIP down-regulates the innate immune response by inhibiting the release of proinflammatory cytokines, chemokines, and nitric oxide by activated macrophages, microglia, and dendritic cells. VIP affects the adaptive immune response by reducing the costimulatory capacity of antigen-presenting cells, and by preferentially inducing Th(2)-type responses. This is accomplished through preferential Th(2) differentiation, enhanced survival of Th(2) effectors, and the induction of Th(2)-attracting chemokines. Recently, we discovered a novel mechanism for the immunosuppressive effect of VIP that involves the generation of antigen-specific regulatory T cells (Treg) through the induction of tolerogenic dendritic cells (tDC). In this work, we review the VIP-induced Treg generation both in vivo and in vitro, and the use of VIP-generated Treg in two models of autoimmunity, i.e., collagen-induced arthritis and experimental autoimmune encephalomyelitis, and in bone marrow transplantation as related to graft-versus-host disease and the graft-versus-leukemia response.