Mechanisms of asthma and allergic inflammation
Omalizumab-induced reductions in mast cell FcεRI expression and function

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Abstract

Background

By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their FcεRI density and function.

Objective

We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab.

Methods

Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and FcεRIα immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein).

Results

Omalizumab recipients, but not control subjects, demonstrated reductions in FcεRIα immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points.

Conclusion

Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil FcεRI receptor expression. In contrast, the time course for the decrease of FcεRI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Section snippets

Subjects

The 3 subjects in this report had a history of moderately severe perennial allergic rhinitis and provided informed consent to venous blood sampling, skin testing, and skin biopsies per protocols approved by the Johns Hopkins Institutional Review Board. Subjects were participants in a phase I trial of omalizumab, as previously reported, and received omalizumab, 0.03 mg/kg/IU IgE/mL, administered intravenously on a bimonthly basis for 6 months.1., 2. In the first week of dosing, these subjects

Serum IgE levels and basophil FcεRIα

These results have been previously published and are noted here to provide background for the mast cell studies. At baseline, the 3 omalizumab recipients had a mean IgE level of 1037 ± 394 ng/mL (432 ± 164 IU/mL). One week after initiation of omalizumab, subjects had an approximately 99% reduction in free IgE levels that was maintained through day 196 (Fig 1, A). As previously reported,1 these subjects also showed an 88% reduction in basophil surface FcεRIα expression 1 week after initiating

Discussion

In earlier reports we demonstrated a clear relationship between free IgE levels and FcεRI expression on blood basophils in allergic subjects undergoing omalizumab infusion. Furthermore, the decrease in basophil FcεRI expression was accompanied by a decrease in basophil histamine response to allergen challenge.1., 2. Separately, a reduction in mast cell FcεRI expression, function, or both was implicated by the reduction in acute skin test size after several weeks of omalizumab infusion,5 and

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Supported in part by National Institutes of Health grants AI01564 and AI045839.

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