Shrey Patel

Background: There are approximately 33 million Americans currently living with food allergies (FA), defined by their characteristic exaggerated immune responses to certain food allergens¹.These unwanted allergic reactions may lead to severe life-threatening medical emergencies such as anaphylactic shock². To prevent the immune response from progressing further, therapies such as the EpiPen and antihistamines exist by counteracting the effects of vasodilation, bronchoconstriction, and urticaria³. These treatments, however, cannot be utilized as preventative measures and are only effective for severe allergic reactions. Thus, the recent discoveries of mast cell-specific immunomodulatory receptors such as the Siglec family and FcgRIIB are promising targets for mitigating allergic inflammation.

Methods: A PubMed database search was conducted for relationships between the following keywords: food allergy, food hypersensitivity, allergic inflammation, mast cell degranulation, anaphylaxis, and mast cell inhibition. These searches were further refined by excluding studies published no more than 5 years prior.

Results: In 2020, investigators synthesized the first high-specificity ligand for the Siglec-3 receptor located on mast cells. They attached this ligand (CD33L) to a liposome (LP) alongside trinitrophenol (TNP) and intravenously injected it into TNP-sensitized mice expressing human LAD2 mast cells. After measuring markers for mast cell degranulation, investigators found that the liposomes studded with CD33L and TNP induced complete suppression of TNP-sensitized mast cell activity, while liposomes absent of CD33L or expressing one of the ligands induced mast cell activation⁴. Thus, it demonstrated that the selective inhibition of mast cells and subsequent allergic inflammation was possible via these inhibitory receptors. This finding was consistent with other allergens such as the peanut allergen, Ara h 2 and the egg allergen, OVA, suggesting the generality of this receptor’s therapeutic potential in vivo. To assess the clinical potential of the Siglec family receptors, a 2021 clinical study administered intravenous doses of Lirentelimab, a Siglec-8 antibody, to patients with chronic urticaria, a condition characterized by hives due to persistent mast cell activation. After comparing the Urticaria Control Test scores (UCT), patients that received Lirentelimab received scores with much less mast cell activation compared to their counterparts across all groups, suggesting that targeting these receptors has high potential for preventing allergic reactions⁵.

Conclusion:  Therapeutically targeting immune modulatory receptors such as Siglecs 3 and 8 on mast cells can selectively suppress mast cell activation to certain allergens and has exciting potential for the prevention and treatment of food allergies.

Works Cited:

1. Lopez CM, Yarrarapu SNS, Mendez MD. Food Allergies. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 24, 2023.
2. Calvani M, Anania C, Caffarelli C, et al. Food allergy: an updated review on pathogenesis, diagnosis, prevention, and management. Acta Biomed. 2020;91(11-S):e2020012. Published 2020 Sep 15. doi:10.23750/abm.v91i11-S.10316
3. Dunlop JH. Oral immunotherapy for treatment of peanut allergy. J Investig Med. 2020;68(6):1152-1155. doi:10.1136/jim-2020-001422
4. Duan S, Koziol-White CJ, Jester WF Jr, et al. CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen. J Clin Invest. 2019;129(3):1387-1401. doi:10.1172/JCI125456
5. Altrichter S, Staubach P, Pasha M, et al. An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria [published correction appears in J Allergy Clin Immunol. 2022 Sep;150(3):736-737]. J Allergy Clin Immunol. 2022;149(5):1683-1690.e7. doi:10.1016/j.jaci.2021.12.772