Food allergy is thought to result from a defect in either the establishment or maintenance of oral tolerance, defined as a state of unresponsiveness upon reencounter with an antigen following oral exposure. T regulatory cells (Tregs) are an important component of oral tolerance, and several studies have suggested that deficits in the development, function, and/or stability of Tregs predispose to food allergy. Adoptive transfer of Tregs can suppress anaphylactic responses to food antigens in murine models, and mice that cannot produce Tregs outside the thymus spontaneously develop type 2 inflammation at mucosal sites and generate an antibody response against antigens found in mouse chow. Loss-of-function mutations in FOXP3, which encodes the main transcription factor essential for Treg development, cause immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome that is associated with profound autoinflammatory disease, as well as food allergy and eczema in some patients. Additionally, an increase in the frequency and stability of Tregs was associated with more favorable clinical outcomes in children who underwent oral immunotherapy for peanut allergy, and increased numbers of Treg were reported in children who naturally outgrew their milk allergy. To further interrogate the role for T cells in the pathogenesis of food allergy, we have developed a novel assay that allows us to simultaneously detect peanut-specific Tregs and T effector (ps-Teffs) cells. Peanut allergy is the number one cause of allergic reactions in the United States, and the prevalence appears to be increasing at an alarming rate. In our preliminary studies, the frequency, stability (as assessed by methylation status of the FOXP3 locus) and tissue homing receptor expression of peanut specific-Tregs in peripheral blood were similar in peanut allergic and non-allergic children. Peanut-specific Teffs from peanut allergic school-aged children were more likely to produce IL-13 and less likely to express IFN- compared to non-allergic controls; however, while peanut-specific Teffs from peanut sensitized or allergic infants were also Th2-skewed, few IFN-+ ps-Teffs were detected in one year old infants regardless of allergic status. Moreover, ps-Teffs from infants sensitized or allergic to peanut at one year of age were more likely to express the skin homing receptor CLA compared to non-allergic controls, suggesting they were likely primed following exposure to peanut through the skin. Our preliminary findings suggest, then, that exposure to peanut through the skin may prime the development of Th2 ps-Teffs that promote sensitization to peanut, despite the presence of normal numbers of ps-Tregs. No FDA-approved treatment for food allergy is currently available. Recent studies suggest that oral immunotherapy (OIT), in which the allergenic food is mixed into a vehicle and then ingested in gradually increasing quantities, may hold promise as a potential treatment for food allergy. However, excitement for this therapy has been tempered by the frequent occurrence of side effects, including severe allergic reactions, and the lack of sustained protection in most subjects once treatment is discontinued. These limitations have sparked investigations into adjunctive therapies, including omalizumab, that would improve both safety and long-term efficacy. Omalizumab is a humanized monoclonal antibody that sequesters free IgE and prevents its binding to the high affinity IgE receptor FcRI. Results of the first double-blind placebo-controlled (DBPC) trial of omalizumab in combination with OIT in patients with severe persistent milk allergy were recently reported. Although omalizumab did not significantly improve the overall rates of desensitization compared to subjects receiving milk OIT (MOIT) alone, omalizumab-treated subjects exhibited significant improvements in nearly all safety parameters. We have now shown that baseline measures of basophil reactivity and the allergen-specific IgE over total IgE ratio can identify a subset of subjects who are likely to benefit the most from adjunctive therapy with omalizumab during OIT in terms of both safety and likelihood of achieving sustained unresponsiveness. We further found that baseline basophil CD63 expression was strongly associated with the occurrence of symptoms during OIT, and may predict a subgroup of patients who will experience the most benefit from omalizumab in reducing adverse reactions.
| Weissler, Katherine A; Rasooly, Marjohn; DiMaggio, Tom et al. (2018) Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut. J Allergy Clin Immunol 141:1699-1710.e7 |
| Frischmeyer-Guerrerio, Pamela A; Masilamani, Madhan; Gu, Wenjuan et al. (2017) Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy. J Allergy Clin Immunol 140:1043-1053.e8 |
| Jhamnani, Rekha D; Frischmeyer-Guerrerio, Pamela (2016) Desensitization for Peanut Allergies in Children. Curr Treat Options Allergy 3:282-291 |
| Happel, Corinne S; Stone, Kelly D; Freeman, Alexandra F et al. (2016) Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8-deficient patients. J Allergy Clin Immunol 137:1895-1898.e5 |
| Keet, Corinne A; Frischmeyer-Guerrerio, Pamela A; Wood, Robert A (2015) Pediatric allergy. Immunol Allergy Clin North Am 35:xiii-xiv |
| Narisety, Satya D; Frischmeyer-Guerrerio, Pamela A; Keet, Corinne A et al. (2015) A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol 135:1275-82.e1-6 |
