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