Omalizumab reverses the phenotypic and functional effects of IgE-Enhanced FcεRI on human skin mast cells

The dramatic effects of the anti-IgE mAb omalizumab to lower free IgE levels and Fc epsilon RI levels on basophils contrast with more modest clinical effects. Accordingly, whether IgE modulates Fc epsilon Rl levels and Fc epsilon RI-dependent mediator release in vitro on human skin mast cells (MCTC type) that had matured in vivo is of interest. IgE reversibly enhanced Fc epsilon RI levels on MCTC cells in a dose- and time-dependent manner (up-regulation t(1/2) of 4-5 days with 1-3 mu g/ml IgE), without affecting cell proliferation. A molar ratio of omalizumab to IgE of 0.9 at baseline prevented receptor up-regulation by 50%, whereas adding omalizumab to MCTC cells already with IgE-enhanced FcERI levels at molar ratios of 5, 12.5, and 31 reduced Fc epsilon RI levels to baseline with respective t(1/2) values of 8.7, 6.3, and 4.8 days. MCTC cells with IgE-enhanced Fc epsilon RI levels were more sensitive to stimulation with a low dose of anti-Fc epsilon RI mAb in terms of degranulation and production of PGD(2), GM-CSF, IL-6, IL-13, and TNF-alpha. Reducing up-regulated Fc epsilon RI levels with omalizumab also reduced mediator release to a low dose of anti-Fc epsilon RI mAb to baseline by 3-4 wk. Thus, reducing free IgE should decrease the hypersensitivity of allergic individuals to low naturally occurring concentrations of allergens.