CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris
Judith R. Abrams, … , Susan L. Kelley, Sewon Kang
Judith R. Abrams, … , Susan L. Kelley, Sewon Kang
Published May 1, 1999
Citation Information: J Clin Invest. 1999;103(9):1243-1252. https://doi.org/10.1172/JCI5857.
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Article

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

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.

Authors

Judith R. Abrams, Mark G. Lebwohl, Cynthia A. Guzzo, Brian V. Jegasothy, Michael T. Goldfarb, Bernard S. Goffe, Alan Menter, Nicholas J. Lowe, Gerald Krueger, Michael J. Brown, Russell S. Weiner, Martin J. Birkhofer, Garvin L. Warner, Karen K. Berry, Peter S. Linsley, James G. Krueger, Hans D. Ochs, Susan L. Kelley, Sewon Kang

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Figure 5

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Absence of increased intralesional apoptosis following administration of...
Absence of increased intralesional apoptosis following administration of CTLA4Ig. Illustrated in a and b are representative negative TUNEL reactions obtained following histochemical examination across all sampling time points and all dose levels of the study. In representative sections from a patient accrued to the 50 mg/kg dose level, no increased rate of in situ cell death was evident when comparisons were made between pretreatment (a) and day 36 (b) lesional biopsies. Scale bar in a: 100 μm. Positive controls included in these experiments are illustrated in c and d, which are paired biopsy specimens from patients receiving ultraviolet B light (UVB) therapy. An increased rate of in situ apoptosis at day 15 (d) compared with baseline examination (c) was seen following daily administration of UVB treatment. Double staining of these sections with mAb’s reactive with CD3 identified the apoptotic cells as T cells.