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Therapeutic manipulation of innate lymphoid cells
Laura M. Cobb, Michael R. Verneris
Laura M. Cobb, Michael R. Verneris
Published March 22, 2021
Citation Information: JCI Insight. 2021;6(6):e146006. https://doi.org/10.1172/jci.insight.146006.
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Review

Therapeutic manipulation of innate lymphoid cells

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Abstract

Since their relatively recent discovery, innate lymphoid cells (ILCs) have been shown to be tissue-resident lymphocytes that are critical mediators of tissue homeostasis, regeneration, and pathogen response. However, ILC dysregulation contributes to a diverse spectrum of human diseases, spanning virtually every organ system. ILCs rapidly respond to environmental cues by altering their own phenotype and function as well as influencing the behavior of other local tissue-resident cells. With a growing understanding of ILC biology, investigators continue to elucidate mechanisms that expand our ability to phenotype, isolate, target, and expand ILCs ex vivo. With mounting preclinical data and clinical correlates, the role of ILCs in both disease pathogenesis and resolution is evident, justifying ILC manipulation for clinical benefit. This Review will highlight areas of ongoing translational research and critical questions for future study that will enable us to harness the full therapeutic potential of these captivating cells.

Authors

Laura M. Cobb, Michael R. Verneris

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Figure 1

Targeting ILCs in diseases of the airway.

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Targeting ILCs in diseases of the airway.
Activated ILC2s accumulate in ...
Activated ILC2s accumulate in the lung in asthma and promote disease via 2 mechanisms: (a) direct activation by TSLP (thymic stromal lymphopoietin), IL-33, and IL-25 in response to allergens, viruses, and environmental stress and (b) IgE-dependent antigen responses, which induce mast cell secretion of lipid mediators, such as PGD2 (prostaglandin D2) and CysLTs (cysteinyl leukotrienes), to attract and activate ILC2s. ILC2s also promote type 2 responses in allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyposis (CRSwNP), where they accumulate in polyps. Seasonal increases in ILC2s in AR are suppressed by allergen immunotherapy. Montelukast (a CysLT1 antagonist), approved for asthma and AR, inhibits ILC2 activation. β2 Adrenergic receptor (β2AR) agonists negatively regulate ILC2s in asthma by inhibiting their proliferation and effector function. In both asthma with or without AR and CRSwNP, systemic steroids decrease ILC2 cytokine production and promote ILC2 apoptosis. Dupilumab inhibits IL-4Rα, the shared receptor of IL-4 and IL-13, and is approved in asthma and CRSwNP. Anti–IL-5 mAbs (mepolizumab, benralizumab, reslizumab) are approved in asthma and are being tested in CRSwNP. CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists to block PGD2-mediated ILC2 trafficking as well as antibodies against TSLP and IL-33 to inhibit ILC2 activation are in testing. Illustrated by Rachel Davidowitz.

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