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* Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106;
Kyoto University Graduate School of Medicine, Kyoto, Japan;
Centocor, Inc., Malvern, PA 19355;
Division of Dermatology, Georgetown University, Washington, DC 20007;
¶ Clinical Research Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901; and
|| Veterans Affairs Medical Center, Cleveland, OH 44106
Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-
) and chemokines (IL-8, IFN--inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-
levels and infiltrating T cells were observed in high responders (improvement in clinical score, 
75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF- significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.
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 This work was supported by National Institutes of Health Grants P30AR39750-14 (to K.D.C. and T.S.M.) and NIH AI41766-09 (to K.D.C.). This study also received funding from Centocor, Inc.
2 Address correspondence and reprint requests to Dr. Thomas S. McCormick, Department of Dermatology, Case Western Reserve University and, University Hospitals of Cleveland, Biomedical Research Building 530, 2109 Adelbert Road, Cleveland, OH 44106. E-mail address: tsm4{at}po.cwru.edu
3 Abbreviations used in this paper: DC, dendritic cell; PASI, Psoriasis Area and Severity Index; IP-10, IFN--inducible protein 10.
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