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Understanding human mast cells: lesson from therapies for allergic and non-allergic diseases

Abstract

Mast cells have crucial roles in allergic and other inflammatory diseases. Preclinical approaches provide circumstantial evidence for mast cell involvement in many diseases, but these studies have major limitations — for example, there is still a lack of suitable mouse models for some mast cell-driven diseases such as urticaria. Some approaches for studying mast cells are invasive or can induce severe reactions, and very few mediators or receptors are specific for mast cells. Recently, several drugs that target human mast cells have been developed. These include monoclonal antibodies and small molecules that can specifically inhibit mast cell degranulation via key receptors (such as FcεRI), that block specific signal transduction pathways involved in mast cell activation (for example, BTK), that silence mast cells via inhibitory receptors (such as Siglec-8) or that reduce mast cell numbers and prevent their differentiation by acting on the mast/stem cell growth factor receptor KIT. In this Review, we discuss the existing and emerging therapies that target mast cells, and we consider how these treatments can help us to understand mast cell functions in disease.

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Fig. 1: Approaches for characterizing the functions of human mast cells in disease.
Fig. 2: Timeline for the development of mast cell-targeted treatments.
Fig. 3: Current targets and relevant mast cell-targeted treatments under development.

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P.K. and M.Ma. conceived the idea for the Review. P.K. researched data for the article and wrote the first version of the manuscript under the supervision of M.Ma., with constructive input from M.Me. and F.S. D.E.-A.-K. prepared figures under the supervision of P.K. and M.Ma., and contributed to the discussion of the content. All authors read and approved the final version of the manuscript.

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Correspondence to Marcus Maurer.

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P.K. was recently a speaker for Novartis and Roche. M.Me. was recently a speaker and/or adviser for Amgen, Aralez, ArgenX, Bayer, Beiersdorf, Celgene, Galderma, Menlo, Moxie, Novartis, Roche, Sanofi, Shire, Siennabio and Uriach. F.S. was recently a speaker and/or adviser for and/or has received research funding from Allakos, Blueprint, Celldex, Genentech, Novartis, Moxie and Uriach. M.Ma. was recently a speaker and/or adviser for and/or has received research funding from Allakos, Alnylam, Amgen, Aralez, ArgenX, AstraZeneca, BioCryst, Blueprint, Celldex, Centogene, CSL Behring, Dyax, FAES, Genentech, GIInnovation, Innate Pharma, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pharming, Pharvaris, Roche, Sanofi/Regeneron, Shire/Takeda, Third HarmonicBio, UCB and Uriach. D.E.-A.-K. declares no competing interests.

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Glossary

Type I hypersensitivity

An IgE and mast cell-mediated allergic reaction in response to environmental antigens (allergens) in sensitized individuals.

β-Hexosaminidase

A mediator stored in mast cell granules, the release of which is measured in mast cell supernatants in vitro in order to determine the degree of cell activation and degranulation upon stimulation with various substances, such as drugs or neuropeptides.

Canakinumab

A recombinant, human anti-IL-1β mAb, approved by the FDA (US Food and Drug Administration) for the treatment of periodic fever syndromes and active systemic juvenile idiopathic arthritis.

Bullous pemphigoid

A chronic autoimmune skin disease characterized by the production of autoantibodies against hemidesmosomal antigens, leading to the formation of subepidermal blisters.

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Kolkhir, P., Elieh-Ali-Komi, D., Metz, M. et al. Understanding human mast cells: lesson from therapies for allergic and non-allergic diseases. Nat Rev Immunol 22, 294–308 (2022). https://doi.org/10.1038/s41577-021-00622-y

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