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An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Authors :
Gisela Torres
Eiko Toichi
Thomas S. McCormick
Kevin D. Cooper
Daniel E. Everitt
Mary Ann Mascelli
Bart Frederick
Catharine L. Kauffman
Timothy Chang
Charles Pendley
Nancy Aria
Alice B. Gottlieb
Source :
The Journal of Immunology. 177:4917-4926
Publication Year :
2006
Publisher :
The American Association of Immunologists, 2006.

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-γ) and chemokines (IL-8, IFN-γ-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-α 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-α 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.

Details

ISSN :
15506606 and 00221767
Volume :
177
Database :
OpenAIRE
Journal :
The Journal of Immunology
Accession number :
edsair.doi.dedup.....dc092042f2a0c88ff02ad4c20bff04ce
Full Text :
https://doi.org/10.4049/jimmunol.177.7.4917