Correction of an in vitro immunoregulatory defect in atopic subjects by the immunostimulating drug fanetizole mesylate (CP-48,810).

Abstract The effect of Fanetizole mesylate or CP-48,810, a new immunostimulating drug, on suppressor cell function and IgE synthesis in vitro was evaluated in atopic patients with allergic rhinitis and/or asthma and eczema. In the absence of the drug, histamine (10 −3 M) stimulated blood mononuclear cells from 23 atopic patients suppressed concanavalin A-induced lymphocyte proliferation by a mean (±S.E.M.) of 9.3%±3.5 (compared to 25.1%±2.7 for histamine stimulated mononuclear cells from non-atopic controls). The addition of the drug (2.5 × 10 −4 M) in vitro significantly increased histamine suppressor cell activity of atopic patients to 26.6%±3.9 (compared to 24.7%±2.8 for control cells in the presence of the drug). In order to determine a possible mechanism through which CP-48,810 might enhance histamine-induced suppressor activity, we examined the effects of the drug on the production of histamine-induced suppressor factor (HSF) by lymphocytes and the production of prostaglandin E 2 by blood monocytes in the presence of HSF. Supernatants generated from histamine (10 −4 M) stimulated patient lymphocytes caused a 9.0% ± 1.8 suppression of concanavalin A-induced lymphocyte proliferation (compared to 25.0%±3.1 caused by supernatants from normal subjects). If the drug (2.5 × 10 −4 M) was added at the beginning of culture, HSF activity in supernatants derived from atopic lymphocytes increased significantly to 20.2%±1.8 (compared to 23.3%±3.9 for drug treated control supernatants). Prostaglandin E 2 production by atopic monocytes exposed to HSF was less than that of normal monocytes in the absence of the drug. The addition of CP-48,810 decreased both basal and HSF-augmented PGE 2 production by both control and atopic cells. Therefore, we could not evaluate this component of the suppressor response further. IgE synthesis in vitro was evaluated in the presence or absence of CP-48,810. B cells from 16 atopic subjects without eczema produced a mean (±S.E.M.) of 516±149 pg/10 6 cells of IgE in the absence of the drug. In the presence of 2.5 × 10 −4 M drug, IgE synthesis was reduced to 196± 70 pg/10 6 cells (68.4% suppression). Blood mononuclear cells from 6 atopic subjects with eczema synthesized a mean (±S.E.M.) 1984±531 pg/10 6 cells of IgE in the absence of the drug. In the presence of 2.5 × 10 −4 M drug, IgE synthesis was reduced to 1486±406 pg/10 6 cells (32.3% suppression). The differing amounts of suppression of IgE synthesis caused by the drug could result either from the greater amount of IgE produced by atopic eczema patients (more difficult to suppress) and/or differing severity of suppressor cell defect in the latter patients. Of note, CP-48,810 did not significantly alter pokeweed-induced IgG synthesis by atopic and control cells. These results suggest that CP-48,810 can partially correct an immunoregulatory defect in atopic subjects, and associated with this finding is a reduction in de novo total IgE synthesis. These findings describe a new potential use for CP-48,810 and in vivo studies appear to be warranted.