Treatment of autoimmune diseases with therapies that tolerize pathogenic lymphocytes may obviate the need for longterm global immunosuppression. In vitro, non-Fc receptor binding derivatives of anti-murine CD3 monoclonal antibodies tolerize type 1 T cells and stimulate type 2 T cells. Recently, a humanized non-FcR binding derivative of the anti-human CD3 Mab OKT3, huOKT3gamma1(ala-ala), has been described. We hypothesized that this Mab may be safe and efficacious in the treatment of type 1 T lymphocyte mediated chronic autoimmune diseases such as psoriatic arthritis (PsA). In a Phase I/II trial, 7 patients with PsA were treated with escalating daily doses of huOKT3gamma1(ala-ala) for 12 to 14 days. Number of tender and swollen joints and a visual analog pain scale were used to rate disease activity at entry and Day 30 and Day 90 after treatment. At Day 30, 6 of 7 patients had > or = 75% improvement in the number of inflamed joints and an average 63% improvement on the patient pain scale. Two of 6 responders had sustained improvement at Day 90. No patient treated with an initial dose < or = 1 mg had significant side effects, nor did they have detectable increases in serum cytokines. One patient treated with 4 mg without escalation developed mild cytokine release symptoms associated with elevation of interleukin 10. Transient T cell depletion occurred following treatment with the maximum dose of 4 mg, which resolved by Day 30. Antiidiotypic antibodies developed in 2 patients; however, there was no concurrent decrease in efficacy. These data indicate that huOKT3gamma1(ala-ala) may be useful in treating PsA.