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dc.contributor.authorPozo, David-
dc.contributor.authorAnderson, Per-
dc.contributor.authorGonzález-Rey, Elena-
dc.identifierdoi: 10.4049/jimmunol.0900400-
dc.identifierissn: 0022-1767-
dc.identifiere-issn: 1550-6606-
dc.identifier.citationJournal of Immunology 183(7): 4346-4359 (2009)-
dc.identifier.otherPMID: 19734220-
dc.description.abstractT regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25- T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs. Copyright © 2009 by The American Association of Immunologists, Inc.-
dc.description.sponsorshipThis work was supported by Spanish Ministry of Education and Science (to E.G.-R.), Spanish Ministry of Health (to D.P.), Junta de Andalucia, and Spanish Collaborative Network on Multiple Sclerosis (ISCIII-RETICS-REEM).-
dc.publisherAmerican Association of Immunologists-
dc.subjectGrowth inhibitors-
dc.subjectVasoactive intestinal peptide-
dc.titleInduction of alloantigen-specific human T regulatory cells by vasoactive intestinal peptide-
dc.description.versionPeer Reviewed-
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