title: IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder.
abstract: The onset of acute psoriasis and the exacerbation of chronic psoriasis are often associated with a history of bacterial infection. We demonstrate that while only few scid/scid mice develop disease when CD4+CD45Rbhigh T cells are transferred alone, coadministration of LPS plus IL-12 or staphylococcal enterotoxin B into scid/scid mice 1 day after CD4+CD45Rbhigh T cell transfer greatly enhances disease penetrance and severity. Most importantly, the skin lesions induced by this method exhibit many of the histologic hallmarks observed in human psoriasis. Skin infiltrating CD4+ T cells were predominantly memory/effector cells (CD45Rblow) and exhibited a highly polarized Th1 phenotype. To test whether the development of pathogenic T cells was dependent on their production of IFN-gamma, we transferred IFN-gamma-/- CD4+CD45Rbhigh T cells into scid/scid or into T, B and NK cell-deficient scid/beige mice. Surprisingly, the incidence of psoriasis was similar to scid/scid animals that received IFN-gamma+/+ T cells, although acanthosis of the skin was attenuated. In contrast, the development of psoriasis was abolished if anti-IL-12 mAb was administered on day 7 and 35 after T cell transfer. Skin-derived IFN-gamma-/- inflammatory cells, but not cells from anti-IL-12-treated animals, secreted substantial amounts of TNF-alpha, suggesting that the inflammatory effect of IFN-gamma-/- T cells may be partly exerted by TNF-alpha and that the therapeutic effect of anti-IL-12 may depend on its ability to down-regulate both TNF-alpha and IFN-gamma. Overall, these results suggest that IL-12, independently of IFN-gamma, is able to induce pathogenic, inflammatory T cells that are able to induce psoriasiform lesions in mice.
authors.affiliation: Protein Design Labs, Inc., Fremont, CA 94555, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Chu
authors.forename: B R
authors.initials: BR
authors.lastname: Lúdvíksson
authors.forename: E L
authors.initials: EL
authors.lastname: Berg
authors.forename: R O
authors.initials: RO
authors.lastname: Ehrhardt
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D012720:Severity of Illness Index; D012867:Skin / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens