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IL-12, Independently of IFN-, Plays a Crucial Role in the Pathogenesis of a Murine Psoriasis-Like Skin Disorder

Kenneth Hong^1,*, Alvina Chu^1,*, Björn R. Lúdvíksson, Ellen L. Berg^* and Rolf O. Ehrhardt^2,*

^* Protein Design Labs, Inc., Fremont, CA 94555; and Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

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⁺CD45Rb^high T cells are transferred alone, coadministration of LPS plus IL-12 or staphylococcal enterotoxin B into scid/scid mice 1 day after CD4⁺CD45Rb^high 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 (CD45Rb^low) and exhibited a highly polarized Th1 phenotype. To test whether the development of pathogenic T cells was dependent on their production of IFN-, we transferred IFN-^-/- CD4⁺CD45Rb^high 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-^+/+ 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-^-/- inflammatory cells, but not cells from anti-IL-12-treated animals, secreted substantial amounts of TNF-, suggesting that the inflammatory effect of IFN-^-/- T cells may be partly exerted by TNF- and that the therapeutic effect of anti-IL-12 may depend on its ability to down-regulate both TNF- and IFN-. Overall, these results suggest that IL-12, independently of IFN-, is able to induce pathogenic, inflammatory T cells that are able to induce psoriasiform lesions in mice.

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