Immune changes beyond Th2 pathways during rapid multifood immunotherapy enabled with omalizumab

Multifood oral immunotherapy (mOIT) with adjunctive anti-IgE (omalizumab, XOLAIR^® ) treatment affords safe, effective, and rapid desensitization to multiple foods, although the specific immune mechanisms mediating this desensitization remain to be fully elucidated.

Participants in our phase 2 mOIT trial (NCT02643862) received omalizumab from baseline to week 16 and mOIT from week 8 to week 36. We compared the immune profile of PBMCs and plasma taken at baseline, week 8, and week 36 using high-dimensional mass cytometry, component-resolved diagnostics, the indirect basophil activation test, and Luminex.

We found (i) decreased frequency of IL-4⁺ peanut-reactive CD4⁺ T cells and a marked downregulation of GPR15 expression and CXCR3 frequency among γδ and CD8⁺ T-cell subsets at week 8 during the initial, omalizumab-alone induction phase; (ii) significant upregulation of the skin-homing receptor CCR4 in peanut-reactive CD4⁺ T and Th2 effector memory (EM) cells and of cutaneous lymphocyte-associated antigen (CLA) in peanut-reactive CD8⁺ T and CD8⁺ EM cells; (iii) downregulation of CD86 expression among antigen-presenting cell subsets; and (iv) reduction in pro-inflammatory cytokines, notably IL-17, at week 36 post-OIT. We also observed significant attenuation of the Th2 phenotype post-OIT, defined by downregulation of IL-4 peanut-reactive T cells and OX40 in Th2EM cells, increased allergen component-specific IgG4/IgE ratio, and decreased allergen-driven activation of indirectly sensitized basophils.

This exploratory study provides novel comprehensive insight into the immune underpinnings of desensitization through omalizumab-facilitated mOIT. Moreover, this study provides encouraging results to support the complex immune changes that can be induced by OIT.