CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris
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
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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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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Reversal of molecular markers of epidermal and vascular pathology follow...
Reversal of molecular markers of epidermal and vascular pathology following administration of CTLA4Ig. Representative immunohistologic findings in the 19 patients demonstrating a 50% or greater improvement in global clinical parameters following administration of CTLA4Ig. Serial biopsies at day 1 (upper row), day 36 (middle row), and day 78 (lower row) obtained from the perimeter of a single representative lesion in a patient accrued to the CTLA4Ig 25 mg/kg dose level. Hematoxylin and eosin–stained sections (labeled H & E in a–c) demonstrate progressive epidermal thinning, diminution in the inflammatory cellular infiltrate, and normalization of keratinocyte maturation on or prior to day 36. Scale bar in a: 100 μm. T cells and proliferating cells present in the psoriatic lesions were detected by immunostaining with mAb’s to CD3 (d–f) and Ki67 nuclear protein (g–i), respectively. A progressive decrease in the number of positively staining cells was evident in the serial biopsies. Expression of keratin 16 (j–l) and α-3 integrin (m–o) in lesional biopsies was reduced following administration of CTLA4Ig. Immunostaining with mAb’s to laminin (p–r), present in the basement membrane of blood vessels, illustrates the serial decrease in the ectasia of the lesional vessels.