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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Reconstitution of the humoral immune response to bacteriophage φX174 in ...
Reconstitution of the humoral immune response to bacteriophage φX174 in the 1 mg/kg, 4 mg/kg, 16 mg/kg, and 50 mg/kg dosing cohorts following tertiary and quaternary immunization. Bacteriophage φX174 was administered at week 1 (1°), week 5 (2°), week 11 (3°), and week 22 (4°). Patient sera were collected before and 1, 2, and 4 weeks after each administration of bacteriophage. Anti-bacteriophage antibody titers were determined by a neutralizing assay and expressed as a rate of phage inactivation, or K value (Kv). Antibody titers for patients accrued to the 1 mg/kg (a), 4 mg/kg (b), 16 mg/kg (c), and 50 mg/kg (d) dose groups are depicted. The geometric mean Kv’s of the 23 psoriatic control patients are illustrated by the dark black line in each part. Vertical bars indicate ±2 SD of the control group mean Kv. Following tertiary and/or quaternary immunization, all patients’ titers were within 2 SD of the control group primary and secondary responses, respectively, with the exception of 1 patient enrolled in the 50 mg/kg dose group (diamonds in d). Despite progressive titer amplification and a immunoglobulin class switch following the 4° immunization, this patient did not achieve the study definition of full reconstitution of the humoral immune response to bacteriophage φX174.