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IL-12/IL-23 in Psoriasis Type 1 Cytokines, Chemokines, and An

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IL-12/IL-23 in Psoriasis Type 1 Cytokines, Chemokines, and An The Journal of Immunology An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis1 Eiko Toichi,*† Gisela Torres,* Thomas S. McCormick,2* Timothy Chang,* Mary Ann Mascelli,‡ Catharine L. Kauffman,§ Nancy Aria,§ Alice B. Gottlieb,¶ Daniel E. Everitt,‡ Bart Frederick,‡ Charles E. Pendley,‡ and Kevin D. Cooper*ʈ 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 Journal of Immunology, 2006, 177: 4917–4926. soriasis vulgaris is a chronic inflammatory skin disease intralesional cyclosporine A (12) all attest to the ongoing and crit- with a complex pathophysiology. The cellular and molec- ical role of intralesional T cell activation. P ular mechanisms underlying the disease involve interrela- Many studies examining the cytokine profile of T cells derived tionships between hyperplastic epidermal keratinocytes and infil- from psoriatic lesions suggest that the type 1 cytokine-producing T trating leukocytes, including memory T cells, neutrophils, cell subset is a prominent component of the lesions (13–17). Pso- 3 dendritic cells (DCs), and macrophages (1–3). The clinical effi- riatic lesions showed elevated mRNA expression for type 1 cyto- by guest on September 30, 2021. Copyright 2006 Pageant Media Ltd. cacy of several interventions targeting T cells, including cyclo- kines (IFN-␥, IL-2, and TNF-␣), compared with lesion-free pso- sporine A (4), Denileukin Diftitox (5), CTLA4Ig (6), and Alefa- riatic skin and normal skin, without a significant component of cept (LFA-3 TIP) (7) demonstrates a critical role of T cell type 2 cytokines (IL-4, IL-5, and IL-10) (18). IFN-␥ was shown to activation in psoriasis, specifically, that of memory/effector cells be an important cytokine involved in the ability of lesional T cell (7). Research using AGR129 mice demonstrated that retained T clones to induce psoriatic uninvolved basal keratinocytes to enter cells in tissue uninvolved by psoriasis could proliferate, leading the cell cycle (13). However, the presence of IFN-␥ does not prove eventually to the development of psoriatic plaques (8). Studies that its role is critical; in experimental autoimmune encephalomy- demonstrating increased activity of lesional APCs (9, 10), their elitis, for example, treatment with anti-IFN-␥ Abs does not result apposition to psoriatic T cells undergoing activation (2), their re- http://classic.jimmunol.org duction during cyclosporine A therapy (11), and the efficacy of in a decrease in clinical severity (19, 20). Further implicating the likely involvement of Th1 cells is the fact that inhibition of TNF-␣, a cytokine that is produced (although not exclusively) by Th1 cells, *Department of Dermatology, Case Western Reserve University, Cleveland, OH results in clinical improvement of psoriasis (21, 22). 44106; †Kyoto University Graduate School of Medicine, Kyoto, Japan; ‡Centocor, Inc., Malvern, PA 19355; §Division of Dermatology, Georgetown University, Wash- IL-12, a heterodimer formed from p40 and p35 subunits, is a key ington, DC 20007; ¶Clinical Research Center, University of Medicine and Dentistry cytokine in Th1 differentiation and proliferation (23–26). Produced of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08901; ʈ Downloaded from and Veterans Affairs Medical Center, Cleveland, OH 44106 by activated APCs (macrophages and DCs, including human epi- Received for publication July 15, 2005. Accepted for publication June 22, 2006. dermal Langerhans cells), IL-12 strongly promotes differentiation ␥ The costs of publication of this article were defrayed in part by the payment of page of naive T cells into IFN- -producing Th1 cells (25, 27–29). It has charges. This article must therefore be hereby marked advertisement in accordance been reported that both IL-12p40 mRNA and IL-12p70 het- with 18 U.S.C. Section 1734 solely to indicate this fact. erodimer are increased in psoriatic skin lesions (30). IL-23, a re- 1 This work was supported by National Institutes of Health Grants P30AR39750-14 cently discovered member of the IL-12 family, is a disulfide- (to K.D.C. and T.S.M.) and NIH AI41766-09 (to K.D.C.). This study also received funding from Centocor, Inc. bridged complex of a unique p19 subunit and the p40 subunit of 2 Address correspondence and reprint requests to Dr. Thomas S. McCormick, De- IL-12 (26, 31). IL-23 possesses similar as well as distinct proper- partment of Dermatology, Case Western Reserve University and, University Hospi- ties from those of IL-12. IL-23 is particularly efficient at inducing tals of Cleveland, Biomedical Research Building 530, 2109 Adelbert Road, Cleve- land, OH 44106. E-mail address: [email protected] the proliferation of memory Th1 cells (31). IL-23p19 transgenic 3 Abbreviations used in this paper: DC, dendritic cell; PASI, Psoriasis Area and Se- mice demonstrate multiorgan inflammation, including skin (32). verity Index; IP-10, IFN-␥-inducible protein 10. Keratin 14/p40 transgenic mice that produce IL-23, but not IL-12, Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4918 ANTI-IL-12p40 THERAPY IN PSORIASIS demonstrate skin inflammation (33), and unlike IL-12, the expres- Immunohistochemical staining sion of IL-23 is critical for experimental autoimmune encephalo- Frozen 5-␮m sections from one-half of skin biopsies were fixed in acetone. myelitis (34). Target organ expression of IL-23, consistent with its Sections were pretreated with PBS containing 0.3% hydrogen peroxide to production by microglia and macrophages, is thought to be critical block endogenous peroxidase activity, and then blocked with 10% normal for its role (35), and importantly, IL-23p19 mRNA is increased in goat serum. Sections were incubated with mouse anti-human CD3 Ab or psoriatic skin (36). mouse anti-human CD11c (IgG2; DakoCytomation) for1hatroom tem- perature. After washing, sections were exposed to a goat anti-mouse bio- Early work in murine models indicates that administration of Ab tinylated secondary Ab (DakoCytomation) for 30 min at room temperature. specific for the IL-12p40 subunit (anti-IL-12p40) can prevent and After subsequent washing, sections were exposed to avidin/HRP (Dako- also ameliorate autoimmune-like conditions (37–44). Anti-IL- Cytomation) for 30 min, washed, and developed with diaminobenzidine 12p40 abolished the development of psoriasis in mice, even when followed by copper sulfate. Sections were then incubated with methyl green or hematoxylin for counterstain. A negative control was established administered after transfer of the T cell subset that induced the using a matched isotype primary Ab and developed as described above. psoriasis-like skin disorder, and led to the down-regulation of Frozen sections were also stained using H&E for assessment of epidermal IFN-␥ and TNF-␣ (44). This is an important finding that suggests thickness. Electronic images were acquired using a Zeiss Axiophot micro- that anti-IL-12p40 may be a valuable treatment strategy against scope and an Axiocam HRc-cooled charge-coupled device camera, con- psoriasis, as well as a good tool in determining whether activated trolled by Axiovision software, version 4.4. Epidermal thickness measure- ment and positive cell counts were performed using computer-assisted T cells critical for psoriasis are indeed Th1 cells and IL-12/IL-23 image analysis. Staining and measurements were performed on 12 of 18 dependent. patients, because sufficient quantity of tissues at multiple time points was Anti-IL-12p40 used in our study is a human IgG1 ␬ mAb that only available for these patients. binds to the p40 subunit of human IL-12 and IL-23 and prevents its Quantitative RT-PCR interaction with IL-12R␤1. This first-in-human study of the ad- ministration of anti-IL-12p40 in patients with moderate-to-severe Total RNA was extracted from one-half of a punch biopsy specimen, and psoriasis vulgaris, showed remarkable clinical responses
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