title: IL-12 and IL-18 act in synergy to clear vaccinia virus infection: involvement of innate and adaptive components of the immune system.
abstract: Development of a protective host response against intracellular pathogens requires innate and cell-mediated immune responses, with cytokines playing an important role in host defences. Different studies in mice have shown that IL-12 can promote protective immunity to a variety of viruses but, during virus infection, little is known about the in vivo function of IL-18 alone or in combination with IL-12. Using recombinant vaccinia viruses (rVVs) expressing IL-12 and IL-18, the antiviral role of both cytokines in mice has been analysed. The specific anti-VV immune response elicited and the persistence of the virus in target tissues were compared in BALB/c mice inoculated with rVVs expressing IL-12 and IL-18 either singly or in combination. Delivery of IL-12 and IL-18 by rVVs in mice induced a significant enhancement in virus clearance from ovaries and spleen, greater than that expected from the sum of action of both cytokines. Virus clearance involved NK and T cells, as demonstrated in mice depleted of NK cells and in immunodeficient SCID animals. Th1 parameters (CD8(+) T cell response and IgG2a : IgG1 ratios) were increased in mice inoculated with rVVs expressing both IL-12 and IL-18 as compared to those animals receiving a single cytokine. These findings indicate that when IL-12 and IL-18 are delivered by rVVs, different mechanisms involving both the innate and specific arms of the immune system act as mediators in the synergistic action of IL-12 and IL-18, leading to VV clearance. These results are of interest for the design of prophylactic as well as therapeutic VV-based strategies.
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, E-28049 Madrid, Spain.
authors.forename: M Magdalena
authors.initials: MM
authors.lastname: Gherardi
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, E-28049 Madrid, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ramírez
authors.affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, E-28049 Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Esteban
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010053:Ovary / Q000276:immunology / Q000821:virology; D011995:Recombination, Genetic; D013154:Spleen / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D014615:Vaccinia / Q000276:immunology* / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D020382:Interleukin-18; D018664:Interleukin-12