The dramatic effects of the anti-IgE mAb omalizumab to lower free IgE levels and Fc epsilonRI levels on basophils contrast with more modest clinical effects. Accordingly, whether IgE modulates Fc epsilonRI levels and Fc epsilonRI-dependent mediator release in vitro on human skin mast cells (MC(TC) type) that had matured in vivo is of interest. IgE reversibly enhanced Fc epsilonRI levels on MC(TC) cells in a dose- and time-dependent manner (up-regulation t(1/2) of 4-5 days with 1-3 microg/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 MC(TC) cells already with IgE-enhanced Fc epsilonRI levels at molar ratios of 5, 12.5, and 31 reduced Fc epsilonRI levels to baseline with respective t(1/2) values of 8.7, 6.3, and 4.8 days. MC(TC) cells with IgE-enhanced Fc epsilonRI levels were more sensitive to stimulation with a low dose of anti-Fc epsilonRI mAb in terms of degranulation and production of PGD(2), GM-CSF, IL-6, IL-13, and TNF-alpha. Reducing up-regulated Fc epsilonRI levels with omalizumab also reduced mediator release to a low dose of anti-Fc epsilonRI 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.