CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

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CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

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Title: CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris
Author: Abrams, Judith R.; Lebwohl. Mark G.; Guzzo, Cynthia A.; Jegasothy. Brian V.; Goldfarb, Michael T.; Goffe, Bernard S.; Menter, Alan; Lowe, Nicholas J.; Krueger, Gerald; Brown, Michael J.; Weiner, Russell S.; Birkhofer, Martin J.; Warner, Garvin L.; Berry, Karen K.; Linsley, Peter S.; Krueger, James G.; Ochs, Hans D.; Kelley, Susan L.; Kang, Sewon
Abstract: Engagement of the B7 family of molecules on antigen-presenting cells with their T cell–associated ligands, CD28 and CD152 (cytotoxic T lymphocyte–associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell–dependent neoantigens, bacteriophage φX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell–dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell–mediated diseases.
URI: http://www.jci.org/articles/view/5857
http://hdl.handle.net/1773/15538

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