An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis.
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.
Toichi
Eiko
E
Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, 2109 Adelbert Road, Cleveland, OH 44106, USA.
Torres
Gisela
G
McCormick
Thomas S
TS
Chang
Timothy
T
Mascelli
Mary Ann
MA
Kauffman
Catharine L
CL
Aria
Nancy
N
Gottlieb
Alice B
AB
Everitt
Daniel E
DE
Frederick
Bart
B
Pendley
Charles E
CE
Cooper
Kevin D
KD
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
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