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

Engagement of the B7 family of molecules on antigen-presenting cells with t heir T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-asso ciated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-ce ll activation. We investigated the role of the CD28/CD152 pathway in psoria sis 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-de pendent neoantigens, bacteriophage phi X174 and keyhole limper hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris rec eived 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). For ty-six percent of all study patients achieved a 50% or greater sustained im provement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was a ssociated with quantitative reduction in epidermal hyperplasia, which corre lated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggestin g that the decreased number of lesional T cells was probably likely attribu table to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antib ody responses to T cell-dependent neoantigens were observed, but immunologi c tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis a nd suggests a potential therapeutic use for this novel immunomodulatory app roach in an array of T cell-mediated diseases.