Inhibition of CD23 processing correlates with inhibition of IL-4-stimulated IgE production in human PBL and hu-PBL-reconstituted SCID mice

Background CD23, the low affinity serum immunoglobulin E (IgE) receptor, is upregulated on B cells following interleukin (IL)-4 stimulation and is con comitantly cleaved to generate soluble CD23 (sCD23) fragments with cytokine -like activity. Objective Compounds that selectively inhibit the proteolytic release of CD2 3 to generate sCD23 were assessed for their ability to inhibit IgE producti on in order to evaluate the contribution of sCD23 in the production of huma n IgE as well as the ability of such compounds to block IgE production. Methods IgE production was measured in IL-4-stimulated human peripheral blo od lymphocytes (PBL) and PBL-reconstituted SCID mice in the presence of a b road-spectrum matrix metalloprotease (MMP) inhibitor, a compound selective for inhibition of CD23 processing over MMPs and an anti-CD23 mAb, MHM6. Results The two compounds were equipotent in inhibiting IgE production with out inhibition of IgG production by IL-4/anti-CD40-stimulated PBL. Soluble CD23 release was also shown to precede IgE accumulation in the cell-free me dium. Addition of compound at later times other than day 0 in the 14 day as say resulted in progressively less inhibition of both IgE and sCD23, and ex actly paralleled the effect of an anti-CD23 mAb, MHM6 on IgE levels. Both c ompounds also inhibited the release of CD23 from human RPMI 8866 cells adop tively transferred i.p. to mice. Doses required for inhibition of CD23 corr elated well with the doses required for inhibition of IgE production in IL- 4-challenged hu-PBL-SCID mice. IgE was selectively inhibited over total IgG in the SCID mice as well. Conclusions Inhibition of CD23 processing alone is sufficient to inhibit IL -4-stimulated IgE production both in vitro and in vivo.