Mast Cell Desensitization in Allergen Immunotherapy

Abstract

Allergen immunotherapy (AIT) is the only treatment with disease-transforming potential for allergic disorders. The immunological mechanisms associated with AIT can be divided along time in two phases: short-term, involving mast cell (MC) desensitization; and long-term, with a regulatory T cell (Treg) response with significant reduction of eosinophilia. This regulatory response is induced in about 70% of patients and lasts up to 3 years after AIT cessation. MC desensitization is characteristic of the initial phase of AIT and it is often related to its success. Yet, the molecular mechanisms involved in allergen-specific MC desensitization, or the connection between MC desensitization and the development of a Treg arm, are poorly understood. The major AIT challenges are its long duration, the development of allergic reactions during AIT, and the lack of efficacy in a considerable proportion of patients. Therefore, reaching a better understanding of the immunology of AIT will help to tackle these short-comings and, particularly, to predict responder-patients. In this regard, omics strategies are empowering the identification of predictive and follow-up biomarkers in AIT. Here, we review the immunological mechanisms underlying AIT with a focus on MC desensitization and AIT-induced adverse reactions. Also, we discuss the identification of novel biomarkers with predictive potential that could improve the rational use of AIT.

Protocol to desensitize human and murine mast cells after polyclonal IgE sensitization

“…This is partly due to the lack of protocols describing MC desensitization and its readouts. Furthermore, current desensitization models largely use murine MCs and monoclonal IgE, while allergic patients present with a polyclonal IgE repertoire ( López-Sanz et al., 2022 ).…”

“…Desensitized MCs can be used directly for co-culture with other cell types, immunofluorescence, live imaging, and omics approaches. For complete details on the use and execution of this protocol, please refer to López-Sanz et al. (2022) .…”

“…For complete details on the use and execution of this protocol, please refer to López-Sanz et al. (2022) .…”

Biomarkers of AIT: Models of prediction of efficacy

“…In AIT, the induction of allergen-specific IgG, IgG4, and IgA, which have IgE-blocking activity, has been well characterized [ 40 ], and their upregulation seems to be in line with clinical symptoms [ 41 ]. The main mechanism involves competitively inhibiting IgE for allergen binding, resulting in the reduction of IgE-induced FcεRI activation on mast cells, thus reducing degranulation and release of inflammatory mediators [ 42 ]. Additionally, binding of allergen-IgE complexes to low-affinity IgE receptors on B cells is inhibited, resulting in diminished IgE-facilitated presentation to T cells [ 40 ] ( Figure 4 ).…”

“…The GRASS trial revealed that SCIT or SLIT is associated with IgG- or IgA-blocking antibodies, respectively [ 15 ]. Humoral biomarkers could be measured both systemically or locally in serum and nasal fluids; and they could be useful to predict local responses characteristic of early AIT response [ 42 ].…”