Therapeutic applications and future perspectives
Pathological processes in food allergy are related to type 2 inflammation, in both IgE mediated and non-IgE mediated diseases. ILC2s have been shown to be key drivers of the pathophysiology. Glucocorticosteroids are often used as therapy and their effect on suppressing ILC2s has been previously demonstrated.122,123 TSLP is related to steroid resistance and blockage with anti-TSLP antibody (AMG157) decreases eosinophilic inflammation in target tissues.124,125IL-25 and IL-33 are also attractive targets for treating allergic diseases. PGI2 analog cicaprost inhibits IL-33-induced ILC2 proliferation in experimental mouse models and decreases IL-5 and IL-13 secretion in humans.126 Blocking of IL-25, IL-33, or TSLP by antibodies like tezepelumab have been reported to be beneficial for treating allergic patients.127 Cytokines released by ILC2s may be targeted to suppress type 2 inflammation. Humanized monoclonal Ab against IL-5 (mepolizumab) and a human Ab against IL-4Rα (dupilumab) were found to be effective against several allergic diseases in humans.128, 129 Dupilumab targets the IL-4R, thereby inhibiting both IL-4 and IL-13 and improves uncontrolled moderate-to-severe atopic dermatitis as well as persistent asthma.130, 131
Many other molecules and pathways relevant to ILC2 activation are also being explored. CRTH2 (CD294), a receptor for PGD2 expressed by ILC2s, promotes ILC2 migration and IL-13 production.132Currently, selective CRTH2 antagonists like fevipiprant and timapiprant are being tested for the treatment of allergic diseases.133, 134 Furthermore, leukotriene receptor antagonists, such as montelukast and zafirlukast can prevent ILC2 activation by inhibiting the cysteinyl leukotriene receptor 1 (CysLT1R).135 Lipoxin A4 (LXA4) functions as an inhibitor of ILC2s136 and severe asthma patients have a LXA4 deficiency137, making LXA4 a treatment option in these patients. Considering that upregulation of c-Myc expression is essential for activation and in vivo pathogenic effects of ILC2s, its inhibition might prove to be a promising novel strategy to combat allergic diseases.138
Regulatory immune cells have also emerged as potential targets, for example Treg cells which can suppress ILC2-driven inflammation. Several recent studies have shown the existence of a novel regulatory ILC counterpart, with the capacity to produce IL-10. These IL-10-producing ILCs are distinct from Treg cells in in vitrostudies139 and can be induced following stimulation with retinoic acid in the periphery. Moreover, these IL-10-producing ILCs are functional and can suppress Th2 cell responses140, 141. These ILCs with regulatory capacity have also been demonstrated to be induced following subcutanous (SCIT) and sublingual grass pollen immunotherapy (SLIT).141These preliminary, yet promising, observations highlight the potential utility of regulatory ILCs as a target for the treatment of food allergy. Finally, possible interaction of ILCs with a novel subset of T cells known as T follicular helper 13 (TFH13) cells which have been implicated in food allergy remains to be identified.143