Abstract
BackgroundAnti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcεRI and CD23 and down regulates FcεRI expression by antigen (Ag) presenting cells (APCs). In addition to its classical role in immediate hypersensitivity, IgE has been shown in vitro to facilitate Ag presentation of allergens, whereby APC bound IgE preferentially takes up allergens for subsequent processing and presentation. The purpose of this study was to determine whether anti-IgE therapy, by blocking facilitated Ag presentation in vivo, attenuates allergen specific Th2 cell responses.MethodsTo test this hypothesis, food allergen specific T cell responses were examined during a 16-week clinical trial of omalizumab in nine subjects with eosinophilic gastroenteritis and food sensitization. Allergen specific T cell responses were measured using carboxyfluorescein succinimidyl ester dye dilution coupled with intracellular cytokine staining and polychromatic flow cytometry. Four independent indices of allergen specific T cell response (proliferation, Ag dose response, precursor frequency, and the ratio of Th2:Th1 cytokine expression) were determined.ResultsEight of the 9 subjects had measurable food allergen specific responses, with a median proliferation index of 112-fold. Allergen specific T cell proliferation was limited to CD4 T cells, whereas CD8 T cell did not proliferate. Food allergen specific responses were Th2 skewed relative to tetanus specific responses in the same subjects. In contradistinction to the original hypothesis, anti-IgE treatment did not diminish any of the four measured indices of allergen specific T cell response.ConclusionsIn sum, using multiple indices of T cell function, this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo.Trial registrationClinicalTrials.gov identifier NCT00084097
Highlights
Anti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcεRI and CD23 and down regulates FcεRI expression by antigen (Ag) presenting cells (APCs)
FcεRI is expressed by dendritic cells (DCs) and monocytes and in this capacity FcεRI may have additional functions beyond immediate hypersensitivity
As an initial approach to determine the effect of in vivo IgE blockade on allergen specific T cell proliferation, we examined the percentage of allergen expanded CFSElow cells at the pre-omalizumab baseline and at the 16-week omalizumab time point
Summary
Anti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcεRI and CD23 and down regulates FcεRI expression by antigen (Ag) presenting cells (APCs). CD23, the low affinity IgE receptor expressed by B cell can preferentially capture IgE bound allergen, resulting in enhanced antigen presentation [3]. Such “IgE facilitated antigen presentation” or “antigen capture” can shift the in vitro T cell proliferation dose response to allergens by 100-1000-fold [2,3]. In a similar manner to TLR9, crosslinking of FcεRI inhibits TLR7 mediated IFN-a expression by human pDCs [5] In both murine and human myeloid DCs, activation by FcεRI crosslinking upregulates CCL28 expression, which is chemotactic for Th2 cells [6,7]. These findings suggest that FcεRI expression by DCs may have multiple consequences, including augmentation of allergic responses and downregulation of virally induced innate immune responses
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