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Omalizumab Reverses the Phenotypic and Functional Effects of IgE-Enhanced FcRI on Human Skin Mast Cells¹

Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, Virginia Commonwealth University, Richmond, VA 23298

The dramatic effects of the anti-IgE mAb omalizumab to lower free IgE levels and FcRI levels on basophils contrast with more modest clinical effects. Accordingly, whether IgE modulates FcRI levels and FcRI-dependent mediator release in vitro on human skin mast cells (MC_TC type) that had matured in vivo is of interest. IgE reversibly enhanced FcRI levels on MC_TC cells in a dose- and time-dependent manner (up-regulation t_1/2 of 4–5 days with 1–3 µg/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 FcRI levels at molar ratios of 5, 12.5, and 31 reduced FcRI levels to baseline with respective t_1/2 values of 8.7, 6.3, and 4.8 days. MC_TC cells with IgE-enhanced FcRI levels were more sensitive to stimulation with a low dose of anti-FcRI mAb in terms of degranulation and production of PGD₂, GM-CSF, IL-6, IL-13, and TNF-. Reducing up-regulated FcRI levels with omalizumab also reduced mediator release to a low dose of anti-FcRI 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from the National Institutes of Health (R01-AI27517), Philip Morris USA, Philip Morris International, and Genentech (to L.B.S.).

² Address correspondence and reprint requests to Dr. Lawrence B. Schwartz, Virginia Commonwealth University, P.O. Box 980263, Richmond, VA 23298-0263. E-mail address: lbschwar{at}vcu.edu

³ Abbreviations used in this paper: SCF, stem cell factor; SBTI, soybean trypsin inhibitor; MFI, mean fluorescence intensity.