JAK1 Inhibition May Treat Patients With Food Allergy

Treatment with a Janus kinase 1 (JAK1) inhibitor may help patients overcome food allergy, according to the results of a study published in The Journal of Allergy and Clinical Immunology. During the study, investigators evaluated the JAK1 inhibitor abrocitinib (Cibnqo; Pfizer) and discovered that it decreases negative immunologic processes that contribute to peanut allergy.¹

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Food allergy is caused by cytokines, including IL-4 receptor α (IL-4Rα) IL-4,IL-13, IL-9, and thymic stromal lymphopoietin (TSLP). These cytokines are responsible for immunoglobulin E (IgE) class switch, mast cell expansion, and produce allergen-specific TH2 cells.

Seeing that multiple cytokines and receptors may be responsible for food allergy, investigators hypothesized that inhibiting JAK1, a signaling molecule downstream of these cytokines, may be a more effective target to stop the manifestation of food allergy compared to targeting any 1 cytokine or receptor in isolation.

For part of this study, investigators measured abrocitnib on basophil activation, an immunologic process that is mediated by IgE and is associated with clinical food reactivity and tolerance. The team looked at CD63 expression to measure basophil activation, observing that the JAK1 inhibitor reduced the allergen-specific response in patients with a peanut allergy.

Investigators also measured how abrocitinib affected patients’ cytokine response in the presence of a peanut. They did this by stimulating the patients’ peripheral blood mononuclear cells (PBMCs) with a peanut for 5 days and observed a statistically significant dose-dependent inhibition in cytokines. The most effective dose for decreasing peanut-specific cytokine response was 100 ng/mL. This was the most effective dose for basophil activation as well.

At doses higher than 100 ng/mL, “abrocitinib may suppress JAK2, which could potentially affect IgE-mediated basophil activation through inhibition of signaling downstream of IL-3,” the study authors wrote.

Yet a smaller dose of 10 ng/mL proved effective for preserving regulatory T (Treg) cell activation. Among 7 patients who experienced a CD37 response in the presence of peanuts, the majority (n=4) did not lose any CD37+ Treg cells, which can act on TH2 cells or allergic effector cells to stop hypersensitivity to food.^1,2

The FDA previously approved abrocitinib for the treatment of moderate-to-severe atopic dermatitis in adults. The agent is currently undergoing other clinical trials, and this study shows that it can be an efficacious treatment as either a monotherapy agent or adjunct to food oral therapy.¹

“These results with basophil activation support the potential role for abrocitinib as a monotherapy in patients with food allergy, whereas the inhibition of TH2 cytokines and T-cell activation support the role of abrocitinib as a potential adjuvant to food oral immunotherapy,” the study authors concluded.¹

Reference

1. Ramsey N, Kazmi W, Phelan M, Lozano-Ojalvo D, Berin CM.JAK1 inhibition with abrocitinib decreases allergen-specific basophil and T-cell activation in pediatric peanut allergy. J Allergy Clin Immunol Glob. 2023 Aug; 2(3): 100103. DOI: 10.1016/j.jacig.2023.100103
2. Lozano-Ojalvo D, Tyler SR, Aranda CJ, et al. Allergen recognition by specific effector Th2 cells enables IL-2-dependent activation of regulatory T cell responses in humans. medRxiv 2022.05.17.22275017; DOI: 10.1101/2022.05.17.22275017