title: An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis.
abstract: 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-gamma) and chemokines (IL-8, IFN-gamma-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-alpha levels and infiltrating T cells were observed in high responders (improvement in clinical score, > or =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-alpha 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.
authors.affiliation: Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, 2109 Adelbert Road, Cleveland, OH 44106, USA.
authors.forename: Eiko
authors.initials: E
authors.lastname: Toichi
authors.forename: Gisela
authors.initials: G
authors.lastname: Torres
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.forename: Timothy
authors.initials: T
authors.lastname: Chang
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Mascelli
authors.forename: Catharine L
authors.initials: CL
authors.lastname: Kauffman
authors.forename: Nancy
authors.initials: N
authors.lastname: Aria
authors.forename: Alice B
authors.initials: AB
authors.lastname: Gottlieb
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Everitt
authors.forename: Bart
authors.initials: B
authors.lastname: Frederick
authors.forename: Charles E
authors.initials: CE
authors.lastname: Pendley
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cooper
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000187:drug effects*; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology* / Q000627:therapeutic use; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000276:immunology*; D021122:Protein Subunits / Q000276:immunology / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C508840:IL23A protein, human; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma