title: Dendritic cells transduced with lentiviral vectors expressing VIP differentiate into VIP-secreting tolerogenic-like DCs.
abstract: Dendritic cells (DCs) initiate immune responses as well as tolerance. We showed previously that the neuropeptide vasoactive intestinal peptide (VIP) suppresses innate immune responses, modulates adaptive responses by generating regulatory T cells (Treg) through the induction of tolerogenic DCs (tDCs), and has therapeutic effects in models of autoimmune/inflammatory disorders. Systemic VIP administration is limited by its short biological half-life and by its pleiotropic effects on the cardiovascular system and gastrointestinal tract. Therefore, we used lentiviral vectors to genetically engineer VIP-expressing bone marrow-derived DC (BMDC) and characterized the transduced LentiVIP-DC in terms of phenotype and therapeutic effects in models of experimental autoimmune encephalomyelitis (EAE) and cecal ligation and puncture (CLP) sepsis. LentiVIP-DCs secrete VIP, and resemble tDCs through lack of co-stimulatory molecule upregulation, lack of proinflammatory cytokine secretion, increased interleukin (IL)-10 production, and poor stimulation of allogeneic T cells. A single inoculation of LentiVIP-DC in EAE or CLP mice had therapeutic effects, which correlated with reduced expression of proinflammatory cytokines and increased IL-10 production in spinal cord and peritoneal fluid, respectively. In contrast to systemic VIP administration that requires repeated, high-dose inoculations, local delivery of VIP by LentiVIP-DC may represent a promising therapeutic tool for the treatment of autoimmune diseases and inflammatory disorders.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Toscano
authors.forename: Mario
authors.initials: M
authors.lastname: Delgado
authors.forename: Weimin
authors.initials: W
authors.lastname: Kong
authors.forename: Francisco
authors.initials: F
authors.lastname: Martin
authors.forename: Mario
authors.initials: M
authors.lastname: Skarica
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005822:Genetic Vectors; D016086:Lentivirus; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic / Q000379:methods*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism*
chemical_list: D014660:Vasoactive Intestinal Peptide