Gomez Gregorio, Jogie-Brahim Sherryline, Shima Mika, Schwartz Lawrence B
Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
J Immunol. 2007 Jul 15;179(2):1353-61. doi: 10.4049/jimmunol.179.2.1353.
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.
抗IgE单克隆抗体奥马珠单抗降低游离IgE水平以及嗜碱性粒细胞上FcεRI水平的显著效果与相对温和的临床效果形成对比。因此，IgE是否在体外调节体内成熟的人皮肤肥大细胞（MC(TC)型）上的FcεRI水平以及FcεRI依赖性介质释放备受关注。IgE以剂量和时间依赖性方式可逆性增强MC(TC)细胞上的FcεRI水平（1-3μg/ml IgE时上调的t(1/2)为4-5天），且不影响细胞增殖。基线时奥马珠单抗与IgE的摩尔比为0.9可使受体上调减少50%，而在已经具有IgE增强的FcεRI水平的MC(TC)细胞中加入摩尔比为5、12.5和31的奥马珠单抗可使FcεRI水平降至基线，各自的t(1/2)值分别为8.7、6.3和4.8天。具有IgE增强的FcεRI水平的MC(TC)细胞在脱颗粒以及PGD(2)、GM-CSF、IL-6、IL-13和TNF-α的产生方面对低剂量抗FcεRI单克隆抗体的刺激更为敏感。用奥马珠单抗降低上调的FcεRI水平也可使低剂量抗FcεRI单克隆抗体诱导的介质释放降至基线水平，持续3至4周。因此，降低游离IgE应会降低过敏个体对低天然存在浓度过敏原的超敏反应。
