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 * Bjo ¨ rn R. Lu ´ dvı ´ksson, ² Ellen L. Berg,* and Rolf O. Ehrhardt 2 * 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, coadmin- istration 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. The Journal of Immunology, 1999, 162: 7480 –7491. P soriasis is a chronic inflammatory skin disease that is as- sociated with hyperplastic epidermal keratinocytes and in- filtrating mononuclear cells, including CD4 + memory T cells, neutrophils, and macrophages (reviewed in Refs. 1–3). Be- cause of this highly mixed inflammatory picture and the resulting complex interrelationships between these different cells, it has been very difficult to dissect the mechanisms that underlie the in- duction and progression of the disease. Indeed, whether genetically determined alterations in keratinocyte proliferation or immuno- regulatory defects are the primary cause of psoriasis is currently unresolved. Some investigators believe that environmental factors, such as microbial infection and trauma, can be an initiating event in the pathogenesis of the disease (4 –7). This hypothesis also im- plies that although dormant autoreactive T cells may pre-exist in susceptible individuals, an environmental stimulus is necessary to trigger disease induction. Others believe that the immune system plays only a minor modulatory role in the disease process and that hyperproliferation of keratinocytes is in fact the initiating event in a genetically susceptible host. Research into the pathogenesis of psoriasis has long been hin- dered by the lack of suitable animal models. Although several rodent models of skin inflammation have been recently introduced, in none of these models have specific T cell abnormalities been demonstrated as a primary cause for the induction of disease (8 – 14). Most recently, Schon et al. (15) presented evidence that a particular splenic T cell subset (CD4 + CD45Rb high ), the same T cell subset that induces colitis in scid/scid mice, is able to induce psoriasis-like lesions when transferred into a minor haplotype mis- matched scid/scid mice. Other investigators have demonstrated that when pre-psoriatic skin, but not skin from healthy donors, is engrafted onto scid/scid mice, the transplanted skin develops into psoriasiform lesions after autologous blood-derived immunocytes are activated by staphylococcal enterotoxin B (SEB) 3 and IL-2 and injected into the dermis (16, 17). In addition, patients that received fragments of diphtheria toxin linked to human IL-2 (DAB389IL- 2), which selectively targets activated T cells but not keratinocytes, showed significant clinical improvement, indicating that T cells and not keratinocytes are the primary pathogenic component in the disease (18). Although these observations provide enough first ev- idence to support the concept that psoriasis-like conditions can indeed result from unregulated T cell responses, they provide very little evidence on the specific mechanism and the cytokines that are involved in the induction of psoriasiform lesions. Bacteria and their products have been implicated as an initiating event in various T cell mediated autoimmune conditions in hu- mans, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) (6, 19). For example, in murine models of RA and IBD, mice do not develop inflammatory lesions under germfree conditions (20 –25). Indeed, either normal luminal bacteria (26) or infection with a single microbial pathogen have been shown to significantly increase the expression of disease (27, 28). LPS and SEB are important bacterial-derived immunomodulators, since they are not only able to activate immune-competent cells but are also able to increase the expression of cell adhesion molecules on vascular endothelial cells and T cells and thereby promote the entry of inflammatory cells into tissues (29 –35). IL-12 produced very early during infection in vivo has important proinflammatory functions. It plays a key role in the differentiation of naive T cells *Protein Design Labs, Inc., Fremont, CA 94555; and ² Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Dis- eases, National Institutes of Health, Bethesda, MD 20892 Received for publication January 25, 1999. Accepted for publication March 29, 1999. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 K.H. and A.C. contributed equally to this work. 2 Address correspondence and reprint requests to Dr. Rolf O. Ehrhardt, Protein De- sign Labs, Inc., 34801 Campus Drive, Fremont, CA 94555. E-mail address: rehrhardt@pdl.com 3 Abbreviations used in this paper: SEB, staphylococcal enterotoxin B; IFN- -/- , IFN--deficient mice; SIL, skin infiltrating lymphocytes. Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00