Recovery from desensitization of IgE‐dependent responses in human lung mast cells

Abstract

Human lung mast cells readily recover from a desensitized state following removal of desensitizing antigen. This finding provides a potential explanation for the ephemeral nature of clinical desensitization.

Rapid desensitization of humanized mice with anti-human FcεRIα monoclonal antibodies

“…One difference between our in vivo results and previous in vitro observations is the ease with which even small doses of anti-hu FcεRIa mAbs decreased expression of both humanized mouse and human mast cell FcεRIa and especially mast cell IgE expression in vivo, although in vitro studies with human mast cells that had been sensitized with IgE and treated with up to 2 mg/mL of anti-IgE mAb failed to show significant loss of mast cell IgE. 36 Although the loss of nearly all IgE by mast cells (and the depletion of basophils) in anti-huFcεRIa mAb-treated mice explains this mAb's ability to suppress IgE-mediated anaphylaxis, the mechanisms involved remain to be determined. IE7 and AER-37, which do not compete with IgE for binding to FcεRI, had a much greater ability to rapidly remove IgE from mast cells than mAbs that compete with IgE for binding, such as 15.1 and IB10, yet IE7 and AER-37 have considerably less ability to remove IgE from mast cells in vitro than in vivo (data not shown).…”

“…Although our studies with huFcεRIa/F709 mice extended our results to a model that may more closely resemble humans who are allergic than the huFcεRIa mouse model, it still studied mouse basophils and mast cells, which have important differences from the homologous human cell types. [36][37][38][39] One important difference, based on in vitro studies, is that it has been more difficult to remove IgE and FcεRIa from the human than the mouse cells by treatment with antigen and anti-FcεRIa mAb. 39 Consequently, it was important to study rapid desensitization with anti-huFcεRIa mAbs in a mouse model that featured human mast cells and basophils.…”

“…Desensitization with anti-FcεRIa mAb instead of the sensitizing antigen offers several advantages: (1) it simultaneously blocks all IgE-mediated anaphylaxis, regardless of the antigen involved, while in vivo antigen desensitization is most typically Ag-specific; 12,36,52 (2) the considerably longer in vivo half-life of IgG antibodies than most antigens [53][54][55] maintains desensitization for a longer period of time without a requirement for additional doses of the desensitizing agent; and (3) desensitization with anti-FcεRIa mAb removes the complication of formation of immune complexes between a desensitizing antigen and preexisting Ag-specific IgG antibodies, including a boosting effect on production of such antibodies. The formation of such complexes may explain the relatively delayed response and greater toxicity of antigen than anti-FcεRIa mAb desensitization (Fig 6, A); initial small doses of the antigen may never reach the mast cell to desensitize it because they are neutralized by Ag-specific IgG antibody.…”

Dependence of Optimal Histamine Release on Cell Surface IgE Density on Human Basophils: Nature of the Stimulus

“…The results shown in Figure 4 differentiate these 2 stimuli: 6061P re-equilibrates rapidly after dilution while BPO 2 (with the BPO-specific IgE in this study) does not. We found a similarly rapid re-equilibration of 6061P when stimulating human lung mast cells [32]. The BPO-EACA results show that the BPO ligand is dissociating rapidly but the crosslink remains “broken” only if there is a vast excess of a monovalent version present; rapid rebinding disallows crosslink “breaking” and retains a signaling-effective crosslink.…”

Developments in the field of allergy in 2017 through the eyes of Clinical and Experimental Allergy

“…155 Following removal of the allergen, the mast cells recovered their effector function within days, suggesting this process of sensitization might be mediated by the temporary accumulation of intracellular inhibitors, as opposed to a fundamental change in the cellular programme, for example, by epigenetic modifications. Clinical desensitization with specific allergens is a common and effective means to induce tolerance; however, this tolerance is not long-lasting and can recur following allergen withdrawal.…”