Therapeutic treatment of experimental colitis with regulatory dendritic cells generated with vasoactive intestinal peptide.
OBJECTIVE
Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon partially caused by a loss of immune tolerance against mucosal antigens. The use of regulatory dendritic cells (DCs) with the capacity to induce regulatory T cells has been proposed recently for the treatment of Crohn's disease in a strategy to restore immune tolerance. Vasoactive intestinal peptide is an immunomodulatory neuropeptide that induces regulatory DCs. The aim of this study was to investigate the therapeutic effect of vasoactive intestinal peptide-induced regulatory DCs (DC(VIP)) in a murine model of colitis.


METHODS
We examined the therapeutic action of DC(VIP) in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid, evaluating diverse clinical signs of the disease including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of DC(VIP), such as inflammatory cytokines and chemokines, Th1-type response, and the generation of regulatory T cells.


RESULTS
DC(VIP) injection significantly ameliorated the clinical and histopathologic severity of colitis, abrogating body weight loss, diarrhea, and inflammation, and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response, by regulating a wide spectrum of inflammatory mediators directly through activated macrophages, and by generating interleukin-10-secreting regulatory T cells with suppressive capacity on autoreactive T cells.


CONCLUSIONS
The possibility to generate/expand ex vivo regulatory DC(VIP) opens new therapeutic perspectives for the treatment of Crohn's disease in human beings, and may minimize the dependence on nonspecific immunosuppressive drugs used currently for autoimmune disorders.
Gonzalez-Rey
Elena
E
Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Cientificas, Granada, Spain.
Delgado
Mario
M
D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D017690:Cell Transplantation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D007108:Immune Tolerance; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D014660:Vasoactive Intestinal Peptide; D014302:Trinitrobenzenesulfonic Acid