# Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases

Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca

Levi-Schaffer

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Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca Levi-Schaffer. Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases. Annual Review of Pharmacology and Toxicology, 2024, 64 (1), pp.481-506. 10.1146/annurev-pharmtox-051623-091038. hal-05030282

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*Annual Review of Pharmacology and Toxicology*

# Novel Immunopharmacological
Drugs for the Treatment of
Allergic Diseases

Ekaterini Tiligada,<fnref n="1" />,<fnref n="2" /> Daria Gafarov,<fnref n="2" /> Maria Zaimi,<fnref n="1" />
Joana Vitte,<fnref n="2" />,<fnref n="3" />,<fnref n="4" /> and Francesca Levi-Schaffer<fnref n="2" />

Annu. Rev. Pharmacol. Toxicol. 2024. 64:481–506

First published as a Review in Advance on
September 18, 2023

The *Annual Review of Pharmacology and Toxicology* is
online at pharmtox.annualreviews.org

https://doi.org/10.1146/annurev-pharmtox-051623-091038

Copyright © 2024 by the author(s). This work is
licensed under a Creative Commons Attribution 4.0
International License, which permits unrestricted
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material in this article for license information.

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Keywords

allergy, biologics, eosinophils, immunopharmacology, mast cells,
small-molecule drugs

Abstract

The exponential rise in the prevalence of allergic diseases since the mid-
twentieth century has led to a genuine public health emergency and has also
fostered major progress in research on the underlying mechanisms and po-
tential treatments. The management of allergic diseases benefits from the
biological revolution, with an array of novel immunomodulatory therapeu-
tic and investigational tools targeting players of allergic inflammation at
distinct pathophysiological steps. Prominent examples include therapeutic
monoclonal antibodies against cytokines, alarmins, and their receptors, as
well as small-molecule modifiers of signal transduction mainly mediated by
Janus kinases and Bruton's tyrosine kinases. However, the first-line thera-
peutic options have yet to switch from symptomatic to disease-modifying
interventions. Here we present an overview of available drugs in the context
of our current understanding of allergy pathophysiology, identify poten-
tial therapeutic targets, and conclude by providing a selection of candidate
immunopharmacological molecules under investigation for potential future
use in allergic diseases.

<footnote n="1">¹Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece</footnote>

<footnote n="2">²Pharmacology and Experimental Therapeutics Unit, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; email: francescal@ekmd.huji.ac.il</footnote>

<footnote n="3">³Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INSERM, Montpellier, France</footnote>

<footnote n="4">⁴IHU Méditerranée Infection, Aix-Marseille University, MEPHI, Marseille, France</footnote>
## INTRODUCTION

Allergy and hypersensitivity are chronic noncommunicable diseases related to environmental exposure and lifestyle (1). Based on 2019 global burden of disease data, the prevalence of asthma and atopic dermatitis (AD) is more than 260 and 170 million cases, respectively (2). The World Health Organization's *International Classification of Diseases 11* dedicated pioneer sections to allergic and hypersensitivity disorders in the immune system chapter (3). Allergy and hypersensitivity comprise numerous disorders, including urticaria (hives), asthma, allergic rhinitis (AR; hay fever), (rhino)conjunctivitis, chronic rhinosinusitis with nasal polyps (CRSwNP), AD (eczema), drug and food allergy, and anaphylaxis, which is an acute, life-threatening medical emergency. These disorders are an abnormal duration and/or intensity of type 2 (T2) immune responses to a stimulus normally tolerated by nonaffected individuals. Unresolved chronic allergic inflammation (ALLINF) creates detrimental changes to the structure and function of the affected organs (4).

ALLINF develops in response to noninfectious, often innocuous, environmental insults and involves a diverse array of cells (Figure 1). Allergen crosslinking of adjacent immunoglobulin (IgE molecules bound to their high-affinity receptors (FcεRI) on sensitized mast cells (MCs) and basophils generates downstream activation signals (5). After MC activation, three distinct consecutive phases are typically observed. The early phase occurs within seconds to minutes and is characterized by the release of predominantly preformed mediators and newly synthesized arachidonic acid metabolites. The late phase takes place after a few hours and involves the migration and infiltration of eosinophils (Eos), macrophages (Mφ), lymphocytes, and other immune cells to the site of MC activation (6). A third (chronic) phase is sustained with the repeated or prolonged exposure to the allergen (4) (Figure 1).

Interestingly, ALLINF shares similarities with ectoparasites and enteric helminth-induced inflammation, including T2 and IgE responses: The epithelial barrier, group 2 innate lymphoid cells (ILC2s) and their adaptive T helper (Th) 2 counterparts build T2 responses. MCs and IgE act as recognized initiators and orchestrators of ALLINF, while Eos serve as its important propagators (7, 8). This simplified interpretation of ALLINF has been enriched through intense research over the past few decades. The new mechanistic insights (endotypes) also provide a better understanding of the complexity of clinical manifestations (phenotypes) (9, 10) (the reader is referred to the sidebar titled Endotypes and Phenotypes of Allergic Inflammatory Diseases). Prominent players of the adaptive and innate T2 immune response, including cytokines, novel MC receptors, and intracellular signaling pathways, provide targets for novel antiallergic drugs (11, 12). Novel pharmacological tools, a few already on the market (Table 1) and others in different stages of

## ENDOTYPES AND PHENOTYPES OF ALLERGIC INFLAMMATORY DISEASES

The diagnosis of allergic and atopic inflammatory diseases relies in most cases on clinical features: evocative symptoms and history and the demonstration of sensitization to the culprit allergen or an atopic background. These clinical features are collectively called phenotype and might be very similar, explaining the empirical one-size-fits-all treatment often prescribed (9). However, we have witnessed in recent years the introduction of the endotype concept, which relates to the pathophysiological mechanisms. Endotype research showed that similar phenotypes might in fact be due to different mechanisms, thus enabling adequate therapeutic targeting of the cells, mediators, and pathways at play in individual patients. Sorting similar phenotypes based on distinct endotypes thus allows the stratification of patients and the prescription of personalized treatments. Personalized treatments allow for better therapeutic control of allergic and atopic diseases. Major lines of research in this field comprise the quest for performant biomarkers of each endotype, in addition to targeted molecules (10).
<figure><img src="image_3.png" /></figure>

(Caption appears on following page)
**Figure 1** (Figure appears on preceding page)

Overview of fundamental, therapeutically relevant processes involved in allergic inflammation. (①) An allergen enters through a compromised epithelial barrier to subepithelial spaces. APCs process the allergen and travel to lymphatic tissue, where they interact with naïve T cells that recognize and bind MHC-II-peptide complexes on the APCs through TCRs. Prolonged T cell responses are sustained through the OX40-OX40L axis. Activated naïve T cells polarize into Th cells that secrete T2 cytokines, including IL-4, IL-5, IL-13, IL-9, and IL-21. Th2 cells interact with naïve B cells, promoting their differentiation into plasma cells and class switch recombination to produce and secrete IgE. Binding of IgE to the high-affinity receptor FcεRI on tissue-resident mast cells and blood-circulating basophils completes the sensitization process. Upon subsequent exposure to the allergen, cross-linking of FcεRI receptors on mast cells triggers their activation. (②) Activated mast cells degranulate, releasing preformed, stored mediators such as histamine and tryptase and newly synthesized prostaglandins and leukotrienes, which are responsible for the immediate signs of allergic inflammation. Subsequently, an array of cytokines, including IL-4, IL-13, IL-3, IL-5, GM-CSF, TNFα, and IL-8, are synthesized and released, giving rise to the late phase and often perpetuating the chronic inflammatory response. (③) The above-described processes enable the recruitment and infiltration of various inflammatory cells, including monocytes, lymphocytes, basophils, neutrophils, and most significantly, eosinophils. (④) Within the inflammation site, abundant mast cells and eosinophils engage in both physical and soluble interactions, creating the Allergic Effector Unit. This multifaceted interaction leads to a further increase in inflammatory activation of both cell types. Activated eosinophils undergo degranulation, releasing cytotoxic secretory mediators such as MBP, EPX, EDN, and ECP. Activated eosinophils also secrete arachidonic acid metabolites and cytokines. Eosinophil-derived cytotoxic mediators contribute to epithelial damage and sustain inflammation. (⑤) In response, the epithelial cells release alarmins such as IL-33, IL-25, and TSLP, which stimulate the production of T2 cytokines by ILC2s, mast cells, and eosinophils. Violet boxes identify secreted factors that are current therapeutic targets. Red arrows indicate secretion or binding. Black arrows indicate resulting effects. Abbreviations: APC, antigen-presenting cell; CD, cluster of differentiation; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPX, eosinophil peroxidase; FcεRI, high-affinity IgE receptor; GM-CSF, granulocyte-macrophage colony stimulating factor; GM-CSFR, GM-CSF receptor; IgE, immunoglobulin E; IL, interleukin; ILC2, group 2 innate lymphoid cells; MBP, major basic protein; MHC-II, major histocompatibility complex class II; MRGPRX2, Mas-related G protein-coupled receptor-X2; OX40L, OX40 ligand; T2, type 2; TCR, T cell receptor; Th, T helper; TNFα, tumor necrosis factor alpha; TSLP, thymic stromal lymphopoietin. Figure adapted from images created with BioRender.com.

development (Table 2), are exemplified by biologics targeting IgE; cytokines such as interleukin (IL)-4, IL-5, and IL-13; thymic stromal lymphopoietin (TSLP) (13) (Figure 2); and inhibitors of intracellular signaling (14) (Figure 3). Additional research in the field has revealed new drug targets such as the Mas-related G protein-coupled receptor (MRGPRX2), the receptor tyrosine kinase c-Kit (CD117), and the sialic acid-binding Ig-like lectin-8 (Siglec-8) (6).

Immunopharmacological research explores new potential therapeutic targets through mecha-
nistic dissection of disease pathogenesis and resolution. This is illustrated by the actions mediated
by the proresolving lipid mediator lipoxin B4 on pivotal cellular effectors for allergy, namely MCs
and Eos (15), and by the demonstration that, upon IgE-mediated activation, both human and
mouse MCs produce resolvin D1 (16), which can provide a negative feedback loop by inhibiting
IgE-induced tryptase release from MCs (P.G. Puzzovio & F. Levi-Schaffer, unpublished data).

This review summarizes recent advancements in the immunopharmacology of allergic diseases and discusses emerging trends and directions of research. Novel and classical pharmacological agents are presented with their targets in ALLINF pathophysiology. Molecules under investigation are also discussed and put in the perspective of expected future developments. Allergen-specific immunotherapy, which is a patient-tailored approach often considered as the only available disease-modifying treatment of allergic diseases (17), is out of the scope of this review.

THERAPEUTIC TARGETS AND TOOLS AT THE EPITHELIAL
AND SENSITIZATION STEPS

The Epithelial Barrier

Sensitization is the first stage of ALLINF development, entailing the initial encounter with en-
vironmental invaders such as pathogens, allergens, and physical or chemical pollutants (1). Many
<table><caption>Table 1 Immunomodulatory drugs approved for the clinical management of allergic diseases</caption><thead><tr><th>Drug (brand name)<sup>a</sup></th><th>Target</th><th>Condition/disease<sup>b</sup></th><th>Reference(s)<sup>c</sup></th></tr></thead><tbody><tr><td colspan="4"><strong>mAbs against IgE</strong></td></tr><tr><td>Omalizumab (Xolair)</td><td>IgE</td><td>Moderate to severe persistent asthma inadequately controlled with ICS<br>CSU nonresponsive to H<sub>1</sub> antihistamines<br>CRSwNP inadequately controlled with nasal corticosteroids</td><td>58, 59, 61, 62</td></tr><tr><td colspan="4"><strong>mAbs against Th2-associated cytokines and their receptors</strong></td></tr><tr><td>Dupilumab (Dupixent)</td><td>IL-4Rα</td><td>Moderate to severe AD<br>Add-on maintenance treatment for severe asthma with type 2 inflammation<br>Add-on therapy for inadequately controlled severe CRSwNP<br>Moderate to severe prurigo nodularis<br>Inadequately controlled eosinophilic esophagitis</td><td>40</td></tr><tr><td>Mepolizumab (Nucala)<br>Reslizumab (Cinqair, Cinqaero)</td><td>IL-5</td><td>Add-on maintenance therapy for severe asthma with eosinophilic phenotype<br>Add-on maintenance therapy for CRSwNP (only mepolizumab)<br>EGPA (only mepolizumab)</td><td>103–105</td></tr><tr><td>Benralizumab (Fasenra)</td><td>IL-5Rα</td><td>Add-on maintenance therapy for severe asthma with eosinophilic phenotype</td><td>98, 108, 109</td></tr><tr><td>Tralokinumab (Adbry, Adtralza)<br>Lebrikizumab<sup>d</sup></td><td>IL-13</td><td>Moderate to severe AD</td><td>42, 44, 45</td></tr><tr><td colspan="4"><strong>mAbs against alarmins</strong></td></tr><tr><td>Tezepelumab (Tezspire)</td><td>TSLP</td><td>Add-on maintenance therapy for inadequately controlled severe asthma</td><td>26, 27</td></tr><tr><td colspan="4"><strong>JAK inhibitors</strong></td></tr><tr><td>Upadacitinib (Rinvoq)<br>Abrocitinib (Cibinqo)<br>Baricitinib (Olumiant)</td><td>JAK</td><td>Moderate to severe AD</td><td>47, 48</td></tr><tr><td>Ruxolitinib (Opzelura)</td><td>JAK</td><td>Topical short-term and noncontinuous chronic treatment of inadequately controlled mild to moderate AD</td><td>14</td></tr></tbody></table>

<footnote><sup>a</sup>Only brand-name medications are stated; brand (trade) names may differ in some countries.</footnote>

<footnote><sup>b</sup>Limitations of use, restrictions, and/or fewer/additional authorized uses may apply for each drug.</footnote>

<footnote><sup>c</sup>Updated information related to the drugs authorized for sale may be obtained at the webpages of the official (inter)national medicines authorities, such as the US Food and Drug Administration (https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases), European Medicines Agency (https://www.ema.europa.eu/en/medicines), Japan Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp), Australian Therapeutic Goods Administration (https://www.tga.gov.au), United Kingdom Medicines & Healthcare products Regulatory Agency (https://products.mhra.gov.uk), and Canadian Drug Product Database (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).</footnote>

<footnote><sup>d</sup>Pending approval.</footnote>

<footnote>Abbreviations: AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyps; CSU, chronic spontaneous urticaria; EGPA, eosinophilic granulomatosis with polyangiitis; IgE, immunoglobulin E; IL, interleukin; IL-4Rα, IL-4 receptor alpha subunit; IL-5Rα, alpha subunit of the heterodimeric IL-5 receptor; ICS, inhaled corticosteroids; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; Th2, T helper type 2; TSLP, thymic stromal lymphopoietin.</footnote>
<table><caption>Table 2 Immunomodulatory drugs at late-phase clinical testing for allergic diseases</caption><thead><tr><th>Drug</th><th>NCT/study phase<sup>a</sup></th><th>Condition/disease</th><th>Mode of action<sup>b</sup></th></tr></thead><tbody><tr><td colspan="4"><strong>mAbs against IgE</strong></td></tr><tr><td>Ligelizumab</td><td>NCT05678959/3<br>NCT04984876/3</td><td>Food allergy</td><td>Next-generation anti-IgE mAb that rapidly neutralizes circulating IgE (90)</td></tr><tr><td colspan="4"><strong>mAbs against cytokines and/or cytokine receptors</strong></td></tr><tr><td>Secukinumab</td><td>NCT02778711/3<br>NCT03568136/2</td><td>Allergic contact dermatitis<br>AD</td><td>Anti-IL-17A mAb that binds to circulating IL-17A, preventing it from interacting with the IL-17 receptor and decreasing Th17 skewing (140)</td></tr><tr><td>CM310</td><td>NCT05265923/3<br>NCT05761028/2/3<br>NCT05186909/2<br>NCT05470647/2<br>NCT05131464/2</td><td>AD<br>Asthma<br>AR<br>CRSwNP</td><td>Anti-IL-4Rα mAb that disrupts IL-4/IL-13 down signaling in type 2 inflammation (137)</td></tr><tr><td colspan="4"><strong>Inhibitors of OX40-OX40L checkpoint interaction</strong></td></tr><tr><td>Rocatinlimab<br>(AMG45, KHK4083)</td><td>NCT05633355/3<br>NCT05651711/3<br>NCT05724199/3<br>NCT05398445/3<br>NCT05704738/3</td><td>AD</td><td>Potential first-in-class anti-OX40 mAb that suppresses and depletes OX40<sup>+</sup>-activated T cells (144)</td></tr><tr><td>Amlitelimab<br>(KY1005, SAR445229)</td><td>NCT05492578/2<br>NCT05769777/2<br>NCT05131477/2<br>NCT05421598/2</td><td>AD<br>Asthma</td><td>Nondepleting anti-OX40L mAb that binds OX40L and blocks OX40-OX40L interaction, aiming at restoring T cell homeostasis (32)</td></tr><tr><td>Telazorlimab<br>(ISB 830, GBR830)</td><td>NCT03568162/2b<br>(completed)</td><td>AD</td><td>Anti-OX40 mAb that inhibits OX40 on activated T cells, attenuating the effects of OX40-OX40L interaction and downregulating active T cells (33)</td></tr><tr><td colspan="4"><strong>JAK inhibitors</strong></td></tr><tr><td>Gusacitinib (ASN002)</td><td>NCT03531957/2b<br>(completed)<br>NCT03728504/2<br>(completed)</td><td>AD<br>Chronic hand eczema</td><td>Oral dual JAK/SYK inhibitor (48)</td></tr><tr><td>Jaktinib<br>(DB17545)</td><td>NCT05676242/3<br>NCT05526222/3</td><td>AD</td><td>Oral JAK1, JAK2, and JAK3 inhibitor (48)</td></tr><tr><td>Ivarmacitinib (SHR0302)</td><td>NCT04875169/3</td><td>AD</td><td>Selective JAK1 inhibitor (154)</td></tr><tr><td>TD-8236</td><td>NCT04150341/2<br>(completed)</td><td>Asthma</td><td>Lung-selective inhaled pan-JAK inhibitor (153)</td></tr><tr><td colspan="4"><strong>Btk inhibitors</strong></td></tr><tr><td>Remibrutinib (LOU064)</td><td>NCT05513001/3<br>NCT05795153/3<br>NCT05048342/3<br>NCT05032157/3<br>NCT05030311/3<br>NCT05677451/3<br>NCT05432388/2</td><td>CSU<br>Food allergy</td><td>Selective covalent Btk inhibitor (155)</td></tr><tr><td>Fenebrutinib<br>(GDC-0853)</td><td>NCT03137069/2<br>completed</td><td>CSU</td><td>Selective, reversible Btk inhibitor (156)</td></tr></tbody></table>

Abbreviations: AD, atopic dermatitis; AR, allergic rhinitis; Btk, Bruton's tyrosine kinase; CRSwNP, chronic rhinosinusitis with nasal polyps; CSU, chronic spontaneous urticaria; IgE, immunoglobulin E; IL, interleukin; IL-4Rα, IL-4 receptor alpha subunit; JAK, Janus kinase; mAb, monoclonal antibody; NCT, National Clinical Trial identification number; OX40L, OX40 ligand; SYK, spleen tyrosine kinase.

<footnote><sup>a</sup>Further and updated information is available at ClinicalTrials.gov (https://clinicaltrials.gov/).</footnote>

<footnote><sup>b</sup>See text for details.</footnote>
<figure><img src="image_4.png" /><figcaption>Figure 2</figcaption></figure>

The art of biologics for targeting allergic inflammation. In the last two decades, therapeutic mAbs targeting different mediators or their receptors on several effector cells involved in allergic inflammation have been developed and approved for clinical use. Examples of the action of the main mAbs that have been approved for the management of allergic diseases are presented here. (a) Tezepelumab neutralizes the alarmin TSLP, thus preventing its interaction with the heterodimeric complex consisting of a TSLPR and an IL-7Rα chain. This prevents TSLP signaling in various cell types, including ILC2s, DCs, basophils, and Th2 cells. (b) Dupilumab binds IL-4Rα, which is the common subunit to IL-4 receptor complexes type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1). This prevents signaling of both IL-4 and IL-13 in various cell types, including B cells, Th2 cells, DCs, fibroblasts, and epithelial cells. Tralokinumab neutralizes IL-13, thus blocking its interaction with both the IL-4 receptor complex type II and IL-13Rα2. Consequently, signaling of IL-13 is inhibited in various cell types, including fibroblasts, keratinocytes, B cells, and DCs, among others. The expression levels of the γc subunit versus the 13-Rα1 subunit differ between hematopoietic and nonhematopoietic cells, which determines whether IL-4 or IL-13 signaling predominates. Hematopoietic cells exhibit relatively higher expression of the γc subunit, whereas nonhematopoietic cells, such as fibroblasts and keratinocytes, present higher levels of the IL-13Rα1 subunit. (c) Omalizumab neutralizes IgE by targeting its Fc, thus blocking IgE-FcεRI interaction and preventing IgE-dependent activation in mast cells and basophils. (d) Mepolizumab and reslizumab neutralize IL-5 and prevent its interaction with the heterodimeric complex consisting of IL-5Rα and βc chain. This prevents IL-5 signaling in various cell types, including eosinophils, basophils, and airway epithelium. Benralizumab is an afucosylated mAb that acts simultaneously through two distinct mechanisms: The Fab domains bind the IL-5Rα of the IL-5R complex, blocking its interaction with IL-5 and preventing downstream signaling. The Fc region of the mAb binds to the IgG receptor FcγRIIIα on macrophages, natural killer cells, and neutrophils, creating a bridge that allows cell killing via ADCC. Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; DC, dendritic cell; Fab, fragment antigen-binding; Fc, constant (crystallizable) fragment; FcεRI, high-affinity IgE receptor; Ig, immunoglobulin; IL, interleukin; Rα, IL receptor subunit alpha; ILC2, group 2 innate lymphoid cell; JAK, Janus kinase; Lyn, a tyrosine kinase; mAb, monoclonal antibody; Th2, T helper type 2; TSLP, thymic stromal lymphopoietin; TSLPR, TSLP receptor; TYK2, tyrosine kinase 2; βc, common beta chain. Figure adapted from images created with BioRender.com.
<figure><img src="image_5.png" /><figcaption>Figure 3</figcaption></figure>

Mechanism of action of JAK inhibitors. Following the binding of a cytokine, receptor subunit dimerization often occurs, as, for instance in the case of IL-4, IL-5, IL-3, and granulocyte-macrophage colony stimulating factor, among others. JAKs, bound to the dimerized receptor subunits, undergo transphosphorylation and phosphorylate intracellular tyrosine residues on the receptor (red arrows). The phosphorylated tyrosine residues then serve as docking sites for STAT proteins, which are also phosphorylated by JAKs. The phosphorylated STATs then dimerize and translocate to the nucleus (black arrows), where they function as transcription factors, regulating various cellular processes, including growth, differentiation, and immune response. Small-molecule JAK inhibitors have emerged as therapeutic strategies for inhibiting the propagation of signal transduction by JAKs, thereby producing immunosuppressive effects. The JAK family encompasses four members, namely JAK1, JAK2, JAK3, and TYK2. JAK inhibitors exhibit varying degrees of selectivity and affinity toward these kinases. Abbreviations: IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription. Figure adapted from images created with BioRender.com.

common allergens, such as house dust mite-derived Der p 1, are proteases that directly affect epithelial cells (ECs) and facilitate the penetration of additional allergens across the epithelial barrier (18, 19). An intrinsically compromised barrier may also contribute to the initiation and progression of ALLINF (20), while loss-of-function mutations in epithelial components, such as filaggrin, are also associated with various allergic conditions (21).
Damaged ECs release alarmins, such as TSLP, IL-33, and IL-25, that initiate T2 responses through ILC2 activation and subsequent production of IL-4 and IL-13 (22, 23). TSLP is also produced by basophils, MCs, Mφ, and dendritic cells (DCs) and exerts its pro-T2 effects through ILC2 cytokine induction, Th2 cell differentiation, basophil development and activation, and Eos activation (24, 25) **(Figure 1)**. TSLP is targeted by tezepelumab (Tezspire), a human IgG2 monoclonal antibody (mAb) that binds TSLP, thereby blocking its interaction with the heterodimeric complex between the TSLP receptor (TSLPR) and the IL-7 receptor α chain (IL-7Rα) (26) **(Figure 2a)**. Tezepelumab was approved in 2021 by the US Food and Drug Administration (FDA) and in 2022 by the European Medicines Agency (EMA) as the first mAb for the management of severe asthma that was not limited to a specific disease phenotype (27). Tezepelumab may thus address the unmet need of patients with T2-low asthma, whereas most immunomodulators are predominantly intended for the eosinophilic phenotypes (28).

## The Sensitization Phase

Moving from the apical surface of the epithelial barrier into subepithelial areas, the allergen is processed by antigen-presenting cells such as DCs and Mφ (29). Mature DCs induce naïve T cell activation and proliferation. The immunological synapse is centered on the major histocompatibility complex class II (MHC-II)-peptide complexes on DCs with T cell receptors and further integrates inputs by innate cell-derived cytokines and costimulatory factors **(Figure 1)**. Expansion, polarization, migration, and function of T cells are affected by costimulatory molecules such as cluster of differentiation (CD)40, CD80, CD86, and CD252 (OX40L) on DCs and CD154 (CD40L), CD28, and CD134 (OX40) on T cells (30). ILC2s also express MHC-II, CD80, CD86, and OX40L and may elicit immunoregulatory effects comparable to those of DCs, such as antigen presentation to effector cells (31). The OX40-OX40L axis may be involved in prolonged T cell responses and shows promise as a therapeutic target (32, 33).

Th2 polarization is promoted by IL-4 in the context of low concentrations of IL-12 and IL-10 (34, 35). The clonal expansion of CD4+ Th2 cells further increases the production of the key T2 cytokines IL-4, IL-5, and IL-13 (30). IL-4, IL-13, and other cytokines activate intracellular signaling pathways via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, leading to increased transcription of genes associated with inflammation **(Figure 3)**. The GATA-binding protein 3 (GATA3) is a master transcription factor for Th2 cell differentiation (36–38). GATA3 is physiologically expressed at low levels, but it is upregulated when STAT6 is activated upon encountering antigen presentation and IL-4 (39). The pivotal role of IL-4 and IL-13 in the initiation of T2 responses and the establishment of ALLINF explains the efficacy of therapeutic mAbs that act at this level. On the other hand, GATA3 intervention downstream of the JAK/STAT pathway explains its indirect targeting by JAK/STAT inhibitors.

Dupilumab (Dupixent) is a mAb of the IgG4 subclass that inhibits signaling of both IL-4 and IL-13 via binding to the IL-4 receptor subunit α (IL-4Rα) **(Figure 2b)**. It was the first targeted biologic to be approved (in 2017–2018) for the treatment of inadequately controlled moderate-to-severe AD. Dupilumab has efficacy and acceptable safety in other T2 pathologies, including asthma, CRSwNP, and eosinophilic esophagitis (40). In 2022, the FDA and EMA approved dupilumab as the first (and only) targeted medicine for children as young as 6 months old with severe AD.

A more recent addition to the group of available biologics, approved in 2021 by the FDA and in 2022 by the EMA, for the treatment of moderate-to-severe AD is tralokinumab (Adbry, Adtralza), an IgG4 mAb that binds to IL-13 and neutralizes its bioactivity (41). Tralokinumab prevents IL-13's interaction with the IL-13 receptor subunit α1 (IL-13Rα1)/IL-4Rα (type II) receptor complex and with IL-13Rα2 **(Figure 2b)**, which has been shown to induce transforming growth factor β
(TGFβ) secretion from Mφ and subsequent fibrosis (42, 43). FDA and EMA approval is pending for lebrikizumab, another IgG4 mAb that also binds soluble IL-13 but does not prevent IL-13 binding to IL-13Rα2 (44, 45).

The impact of JAK/STAT signaling on AD pathogenesis led to the clinical exploitation of the immunosuppressant JAK inhibitors upadacitinib (Rinvoq) and abrocitinib (Cibinqo®) for systemic and topical use (46) with baricitinib (Olumiant®), which is under FDA review (47, 48) (Figure 3).

## IgE and the FcεRI

Class switch recombination of B cells to produce and secrete allergen-specific IgE antibodies is driven by Th2 and T follicular helper cells through T2 cytokines, including IL-4, IL-5, IL-13, IL-21, and IL-33 (49, 50). Specific IgE memory persists for years, even in the absence of further allergen challenges (51, 52).

Compared to the other Ig subclasses, IgE exhibits unique features, such as low serum concentration, long half-life in tissues, and a primary mode of action through binding to cell surface receptors rather than to complement fractions (53). IgE binds to FcεRIs ($K_d$ ~1 nM) that are predominantly localized on MCs and basophils (Figure 1). The strong FcεRI-IgE interaction along with the high abundance of the receptor on these cells (~$10^5$ per cell) ensures that the receptors are almost always occupied (53). Moreover, binding of IgE to the FcεRI upregulates surface receptor levels, thereby serving as a feedback loop that reduces the concentration of allergen needed for activation in atopic individuals (54, 55). Likewise, interaction of IgE with the low-affinity IgE receptors (FcεRII or CD23) ($K_d$ 0.1–1 µM), expressed on ECs, B cells, and other cells, may contribute to the regulation of IgE production and availability. Binding of IgE to the Fcε receptors completes the sensitization phase and allows an active ALLINF upon subsequent encounters of the allergen.

Omalizumab (Xolair), a recombinant humanized IgG1 mAb targeted to the constant (crystallizable) fragment (Fc) of IgE, prevents the binding of the Fc of the IgE molecule to the FcεRI on MCs, basophils, and other immune cells (Figure 2c), thereby reducing free IgE (56, 57). Omalizumab was approved by the FDA and the EMA in 2003 and 2005, respectively, for patients with IgE-mediated asthma (58). Since 2014, omalizumab has been indicated as add-on therapy for the treatment of chronic spontaneous urticaria (CSU) in patients with inadequate response to $H_1$ antihistamines (59, 60). Furthermore, in 2020 it was approved as add-on therapy for the treatment of severe CRSwNP inadequately controlled with intranasal corticosteroids (61, 62). Omalizumab was the first biologic to offer the option of self-administration by the EMA in 2018.

## THERAPEUTIC TARGETS AND TOOLS IN THE INFLAMMATORY PHASE

### MC Activation

MCs are heterogeneous, granulated innate immune cells of the myeloid lineage that arise from CD34⁺ CD117⁺ (c-Kit) progenitor cells (63). MC progenitors circulate in the blood and are driven by stem cell factor (SCF), the ligand of the c-Kit tyrosine kinase receptor, to the tissue where they fully differentiate into long-lived resident cells (63–65). Upon maturation in peripheral tissues, MCs express a variety of surface receptors, including CD117, FcεRI, and numerous activating and inhibitory ones, such as MRGPRX2, CD48, toll-like receptors (TLRs) 2 and 4, and CD300a, Siglec-6, -7, -8, and -9, respectively (6, 66). The variable repertoire of surface receptors along with their strategic positioning at the host-environment interface and around blood vessels facilitates the pivotal roles of MCs in human pathophysiology. MCs act as first-line immediate defenders against a diverse range of triggers and are important contributors in vascular regulation in inflammation (67–71). MCs can respond quickly upon cell activation (Figure 1), mainly by
releasing granular preformed inflammatory mediators, including histamine, proteases, and proteoglycans (6). Histamine, the most prominent MC preformed mediator, is a biogenic amine produced from L-histidine through the catalytic activity of histidine decarboxylase in histamine-producing MCs and basophils (72–74). Histamine's numerous actions are mediated through four G protein-coupled receptor (GPCR) subtypes: H₁, H₂, H₃, and H₄ (72, 74, 75). H₁ receptors in an active state stimulate the early phase of the allergic response, which is characterized by vasodilation, erythema, and edema, followed by increases in the production of cytokines during the late phase. Tryptase, the most abundant protein in MCs, is released upon MC activation as tetramers that increase vascular permeability and smooth muscle contractility, activate protease-activated receptor (PAR)-2, interact with neurons, and exert other proinflammatory actions (76, 77).

Activated MCs also rapidly release newly generated arachidonic acid-derived leukotrienes (LTs) and prostaglandins (PGs), which contribute to the early and late phases of ALLINF through their effects on bronchial and vascular smooth muscle, ILC2 and Eos recruitment, and T2 cytokine production (6, 78, 79).

Intracellular signal transduction in MCs proceeds through a complex network of signaling molecules (5, 80). Along with the crucial roles of the tyrosine kinases Lyn, Syk, and Fyn and the linker for activation of T cells (LAT), mitogen-activated protein kinases (MAPKs) and the non-receptor Bruton's tyrosine kinase (Btk) are key players downstream of FcεRI activation, explaining the efficacy of kinase inhibitors in MC-related diseases (81–83).

MCs' production and response to key drivers of ALLINF, such as IL-4 and IL-13, orchestrate immune cell recruitment at ALLINF sites (84). Consequently, MCs, their activators, their preformed and newly produced mediators, and the receptors thereof are relevant therapeutic targets, harnessed by both classic and novel antiallergic treatments.

First introduced in the 1940s, H₁ antihistamines still constitute the first-line treatment for AR, allergic conjunctivitis, and urticaria, whereas their efficacy in AD, asthma, and anaphylaxis is rather limited (85). Newer generations of oral and/or intranasal H₁ antihistamines either alone or in combination with systemic or topical corticosteroids are the first-line treatment for patients with mild AR (86). Similar to AR, topical treatment of mild allergic conjunctivitis includes ocular instillation of over-the-counter H₁ antihistamines. New-generation, non-sedating H₁ antihistamines are also recommended as the first-line treatment, and with up to fourfold up-dosing as second-line treatment, for chronic urticaria (60).

MC stabilizers that inhibit MC degranulation include cromolyn sodium and nedocromil sodium, which are in use as topical, albeit not particularly efficacious, treatments for AR and allergic rhinoconjunctivitis (87).

LT receptor antagonists are mainly represented by montelukast, introduced in 1998, which ameliorates bronchial and nasal symptoms in patients with AR and asthma (88, 89). The use of zileuton, an inhibitor of lipoxygenase, is hampered by its limited commercial availability (89).

Available immunopharmacological tools indirectly targeting MCs include the anti-IgE mAbs omalizumab and ligelizumab that effectively decrease MC activation by preventing free IgE binding to FcεRI (57–59, 90).

Targeting c-Kit by antityrosine kinase molecules, such as midostaurin and avapritinib, is an effective therapeutic tool for clonal MC diseases such as systemic mastocytosis; however, their use in allergic disease has not yet been established (81–83, 91).

## Eosinophils

Like MCs, Eos are granulated innate immune cells of myeloid origin, developed from multipotent hematopoietic stem cells in the bone marrow (92, 93). However, unlike MCs, Eos circulate in the bloodstream in their mature form and have a relatively short half-life (94, 95). Among Eo
surface receptors, the high-affinity α subunit of the IL-5 receptor (IL-5Rα/CD125) facilitates the differentiation of committed progenitors exclusively into Eos (92, 95).

In addition to multiple bioactive molecules, including eicosanoids and cytokines, the human Eo cytoplasmic granules contain cationic proteins such as major basic proteins (MBPs), eosinophil peroxidase (EPX) and the cationic ribonucleases, eosinophil-derived neurotoxin (EDN/RNase2), and eosinophil cationic protein (ECP/RNase3) (96). Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10) is an abundant constituent of human Eos with key functions in vesicular packaging and degranulation in ALLINF (97). Through discharge of their granules, Eos exert their classic role of protecting the host against parasitic infection and contribute as key functional players in ALLINF and eosinophilic syndromes (95, 98).

In ALLINF, ILC2s and Th2 cells are major sources of IL-5 (7, 22), whereas MCs add to the in situ IL-5 pool as part of the complex interaction between MCs and Eos (99). IL-5 binds to the transmembrane IL-5 receptor (IL-5R) consisting of IL-5Rα and a β chain (CD130). The latter is shared with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors (100). Notably, the α chain also exists as a soluble form (sIL-5Rα) that antagonizes IL-5R signaling; the balance between the expression of the IL-5Rα and sIL-5Rα variants affects Eos sensitivity toward IL-5 (101). IL-5/IL-5R intracellular signaling proceeds through the JAK/STAT and MAPK pathways for Eo development, migration, survival, and activation.

Therapeutic research on Eos was fostered by observations that include massive Eo influx in the late-phase allergic reaction, high prevalence of the eosinophilic phenotype in patients with severe asthma, and a direct relationship between eosinophilia, exacerbation risk, and poor disease control. IL-5 and IL-5R-targeted drugs aim at Eo depletion or attenuation as a strategy to manage eosinophilic airway inflammation in allergic asthma (102). Mepolizumab (Nucala), a humanized IgG1 mAb, binds IL-5 and impairs its interaction with the receptor and reduces Eo production and survival (**Figure 2d**). It was the first anti-IL-5 biologic agent approved (in 2015) by the FDA and EMA for the treatment of patients with severe eosinophilic asthma (103–105). Reslizumab (Cinqair, Cinqaero), another anti-IL-5 mAb (**Figure 2d**), was approved a year later for the same indication (106). A pool of residual circulating Eos, probably of the resident type, are observed following mepolizumab treatment (98, 107).

An alternative approach to IL-5-neutralizing agents is benralizumab (Fasenra), which blocks IL-5 interaction with the IL-5Rα by binding the fragment antigen-binding domain (**Figure 2d**), thereby inhibiting Eo differentiation and maturation (108). In parallel, being an afucosylated IgG1 molecule, benralizumab binds via the Fc region to the IgG receptor FcγIIIa on Mφ, natural killer (NK) cells, and neutrophils, thus inducing antibody-dependent, cell-mediated cytotoxicity (ADCC) (**Figure 2d**) in both circulating and tissue-resident eosinophils (109). Benralizumab was approved by the FDA in 2017 and the EMA in 2018 for the treatment of patients with severe eosinophilic asthma (98).

Besides IL-5, eotaxin-1 (also known as CC-chemokine ligand 11 (CCL11)) is a key chemotactic factor guiding Eos migration from homing tissues to sites of T2-dominated inflammation (98, 110). CCL11 levels have been associated with disease activity and severity in AR (111) and asthma (112), but we are not aware of available or investigational drugs that target CCL11.

## The Allergic Effector Unit

In an ALLINF environment, abundant MCs and Eos in the tissue engage in bidirectional cross talk, exerting stimulating effects on each other's activation state through physical and soluble interactions (**Figure 1**). This crucial cellular interplay, which we have termed the allergic effector unit (AEU) (113), facilitates recruitment, survival, and activation of both cell types and plays a significant role in modulating the course of ALLINF. Consequently, targeting this interaction may
offer novel therapeutic strategies for managing allergic diseases, either by blocking its activating components or by activating its inhibiting components (114).

Physical interactions between MCs and Eos are carried out by their respective cell-surface receptor/ligand couples, with CD48 and 2B4 (CD244) playing a notable role. CD48 is a glycosylphosphatidylinositol-anchored costimulatory receptor with a broad expression pattern across immune cells, including MCs, Eos, and basophils (115). Eos and a number of other cells express its high-affinity binding ligand 2B4 (115). Binding of MC CD48 to Eo 2B4 increases MC activation and Eo survival. CD48 upregulation has been detected on peripheral blood Eos from asthma and AD patients and on Eos from nasal polyps of asthmatic patients (116–118). Even though the inhibitory receptors CD300a and Siglec-7 and their ligands are expressed on both MCs and Eos (80, 119–123), we do not observe reciprocal inhibitory effects between MCs and Eos, further supporting the proinflammatory role of the AEU (P.G. Puzzovio & F. Levi-Schaffer, unpublished data).

The characterization of MC and Eo inhibitory receptors suggests that an ideal MC stabilizer would be a mAb that enhances the inhibitory effect of these receptors. As a proof of concept, we found that bispecific mAbs that target both an activating and an inhibitory receptor on a relevant cell (MC, Eo, or basophil) downregulate ALLINF in vitro and in vivo (119, 120).

The rich array of immune cells involved in ALLINF explains the effectiveness of glucocorticoids, a classic treatment for allergic diseases and the most potent anti-inflammatory drugs that inhibit transcription of proinflammatory cytokines and increase effects of anti-inflammatory transcription factors (124). Prolonged systemic use of glucocorticoids is associated with serious adverse effects; thus, their use is ideally limited to short intervals. Topical formulations, such as inhaled or intranasal glucocorticoids, are widely used in asthma and in moderate-to-severe AR, where they achieve disease control in most but not all patients (124).

More recently, the exploitation of the fundamental function of cyclic adenosine monophosphate (cAMP) as a second messenger in the downstream signaling of multiple cells has been a breakthrough in the discovery of drugs for the management of inflammatory diseases (125). Intracellular cAMP levels are regulated by the activities of adenylyl cyclases and phosphodiesterases (PDEs). Among the PDE enzymes, the cAMP-specific PDE4 is highly expressed in smooth muscle, keratinocytes, and immune cells, including T cells, monocytes, Mφ, neutrophils, DCs, and Eos (126, 127). The capability of selective PDE4 inhibitors to maintain immune balance by elevating intracellular cAMP levels and to modulate inflammation led to the approval of some of them, despite the limitations stemming from their unfavorable side effect profile, and a number of related clinical trials are underway (125). With respect to allergic diseases, the topical formulation of crisaborole (Eucrisa, Staquis) received marketing authorization by the FDA in 2016 for the treatment of AD, whereas it was withdrawn in the European Union in 2022. On the other hand, apremilast and roflumilast failed to demonstrate efficacy for AD in Phase II clinical trials (128), and roflumilast was not approved for the treatment of asthma as it showed adverse effects and comparable efficacy to corticosteroids (129).

## INVESTIGATIONAL DRUGS FOR ALLERGIC DISEASES

Despite the therapeutic options made available in recent years, meaningful improvements for allergic and/or corticosteroid-resistant patients are not always achieved. The poor predictive data from the available animal models, the knowledge gaps in immune and inflammatory pathophysiology, and the yet elusive pharmacological properties of drug candidates and their cellular and molecular targets hamper, at least in part, the efforts to identify efficacious medicines for unmet clinical needs (130). While the evaluation of the numerous animal models used in immunopharmacological research is out of the scope of this review, it is important to consider limitations of
the inter- and intraspecies and strain variations before extrapolating preclinical data to clinical
settings (131). For instance, mice are the gold standard for asthma models, although they do not
develop allergic airway disease spontaneously (132). Ovalbumin and allergen challenge are the
mainstay disease models that have provided vital knowledge on the Th2 phenotype, despite con-
cerns related to the complexity, heterogeneity, and diversities in the immune response, particularly
in chronic inflammation (130, 132). Interestingly, data derived from various MC-deficient models
revealed discrepancies in and controversies surrounding the contribution of MCs in a number of
inflammatory pathologies (133), thus further emphasizing the need for the cautious interpretation
of animal data in predicting human responses.

Approximately 30% of patients with severe asthma do not respond satisfactorily to classic med-
ications nor to tailored biologics (134). Numerous observational studies to assess the beneficial
outcomes of new therapeutic interventions and clinical trials to identify more efficacious and safe
treatments for allergic conditions are in progress (135). Continued research in this area is reflected
by the novel immunomodulatory agents entering clinical evaluation and by attempts to reposition
suitable biologics and small-molecule drugs within the spectrum of allergic and hypersensitivity
disorders (136).

Biologics and Other Novel Immunotherapeutics

Off-label drug use can address unmet medical needs and drives drug repositioning (136, 137). For instance, it has been suggested that Th17 and/or Th1 effector cells are characteristic of noneosinophilic asthma phenotypes (138), whereas increased Th17 skewing was shown in some AD subtypes, and Th17-related markers have been correlated with AD severity (139). Secukinumab (Cosentyx) is a human mAb that was approved in 2014 for the treatment of psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis. Secukinumab binds to circulating IL-17A produced by various cells, including MCs, Mφ, neutrophils, and Th17 cells, and prevents its interaction with the IL-17 receptor. Hence, secukinumab entered Phase II clinical trials for the treatment of AD and is currently in a Phase III study for its efficacy in contact dermatitis (140). Secukinumab and other mAbs with different targets are also being evaluated in observational, systems medicine-designed studies to identify regulatory networks, biomarkers, and association with disease endotypes in psoriasis and AD (NCT03358693).

ClinicalTrials.gov is a major registry and results database that reflects the ongoing trend in the clinical development of potentially useful medicines. A search of the database for relevant trials from 2014 to 2023 revealed that the studies that failed or were terminated for various reasons (128, 141) outnumbered those that advanced into late-stage testing. For instance, drugs targeting the alarmin IL-33 or its receptor entered clinical evaluation, but they have not as yet advanced to late-phase trials (142, 143).

In contrast, the OX40-OX40L axis is a putative therapeutic target that may be exploited for
the management of T2 inflammation, as exemplified by the progressive improvements in AD
upon treatment with OX40 pathway inhibitors such as rocatinlimab (32, 33, 144). Immune check-
point molecules hold paramount significance in orchestrating and modulating immune responses.
The use of immune checkpoint inhibitors in cancer therapy is associated with immune-related
adverse effects, such as the development or exacerbation of atopic-like presentations, including
pruritus and asthma. Thus, it is reasonable to assume that employing immune checkpoint agents
using the opposite approach, that is, activating inhibitory immune checkpoint molecules, can be
useful in the management of ALLINF. Indeed, accumulating evidence supports their beneficial
effects in preclinical allergy models and in humans. For example, treatment with a programmed
cell death protein 1 (PD-1) agonistic mAb reduced airway hyperreactivity in a humanized mouse
model of lung inflammation by repressing pulmonary ILC2s (145). In a similar approach, com-
plement C1q, an endogenous agonist of the inhibitory immune checkpoint leukocyte-associated
immunoglobulin-like receptor 1 (LAIR-1), reduced airway hypersensitivity in a humanized mouse
model through suppression of human ILC2 cytokine secretion, thereby resulting in a conse-
quential reduction in eosinophilia (146). The LAIR-1 receptor transmits inhibitory signals via
intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs), a characteristic feature
shared by many inhibitory receptors. MCs and Eos possess an extensive repertoire of ITIM-
containing receptors. Siglec-6, -7, -8, and -9 are ITIM-bearing inhibitory receptors, expressed
on MCs and/or Eos, and a substantial body of research has demonstrated their potential as valu-
able targets in the context of allergic diseases. In vitro studies using agonistic mAbs demonstrated
Siglec-6-mediated MC inhibition (147) and Siglec-7-mediated reduction in Eo EPX, TNFα, and
IL-8 release following GM-CSF stimulation (122). Recently, Miralda et al. (66) provided evidence
for Siglec-9 expression in human MCs, with dampening of IgE-dependent degranulation. Signif-
icant progress in this area led to the development of lirentelimab, a humanized, nonfucosylated
IgG1 anti-Siglec-8 mAb, which targets Eos through agonistic Siglec-8 signaling and induction
of ADCC. Lirentelimab is currently under clinical investigation in CSU and in eosinophilic
esophagitis, eosinophilic gastritis, and eosinophilic duodenitis (81).

Although exploitation of inhibitory receptors opens new prospects for therapeutic interven-
tions in the field of ALLINF, this approach should be carried out with caution. Given that many
immune checkpoint inhibitory molecules are also expressed on regulatory cells, activation may
suppress regulatory mechanisms and lead to exacerbation of the immune/inflammatory process.
Moreover, intervention in the ability of the immune response to occur leads to the risk of weaken-
ing antitumor immunity. Thus, a strong candidate for a therapeutic target should possess selective
expression on effector cells involved in ALLINF. Utilization of bispecific antibodies that link the
inhibitory receptor to cell-specific activating receptors can further improve this therapeutic ap-
proach. This design of bispecific antibodies not only enhances specificity toward effector cells
but also ensures the proximity of inhibitory dephosphorylation to the activating signaling path-
way. Our group has demonstrated this concept by using bispecific antibodies targeting CD300a
and MC/Eo-specific markers. CD300a is an ITIM-containing receptor, expressed on cells of both
myeloid and lymphoid lineages, with constitutive expression in MCs and Eos. We have previously
demonstrated that human CD300a inhibits IgE-dependent activation, with a much stronger ef-
fect when cross-linked with FcεRI (148). Similarly, we have shown inhibition of differentiation
and survival of human MCs when CD300a was cross-linked with c-Kit via a bispecific Ab (119).
Selectively targeting CD300a on Eos via a bispecific Ab that also recognizes CCR3 resulted in the
reversion of pulmonary inflammation and remodeling in a murine model of asthma (149). These
discoveries highlight the remarkable potential of harnessing bispecific antibodies as a powerful
tool to strategically target immune checkpoint molecules involved in ALLINF.

Other potentially useful targets are also under investigation. Barzolvolimab (CDX-0159), a
humanized IgG1 anti-Kit mAb that prevents SCF binding, resulted in clinical improvement of
chronic inducible urticaria (150) and is undergoing clinical evaluation for eosinophilic esophagi-
tis and CSU. Anti-tryptase mAbs, such as the full-length humanized IgG4 MTPS9579, which
dissociates the active tryptase tetramer into inactive monomers, potentially improving anaphy-
laxis, asthma, and CSU, are also under investigation (151, 152). Ligelizumab is a humanized IgG1
anti-IgE mAb that was recently discontinued from a Phase III trial in CSU but is still under
investigation for the management of patients with food allergy (90).

Small-molecule drugs that modulate immune responses by targeting intracellular signaling
offer attractive alternative therapeutic interventions to mAb biologics for attenuating ALLINF.
These mostly include formulations for systemic or topical administration of a number of JAK
inhibitors with various selectivity (48, 153, 154) and novel Btk inhibitors [e.g., remibrutinib (155) and fenebrutinib (156)] that are currently under clinical investigation for CSU.

Small Molecules Targeting G Protein–Coupled Receptors

The key druggable properties of GPCRs have shaped the success of over one-third of the ap-
proved small-molecule medicines targeting this receptor family. The potential for various GPCRs
to modulate the immune system, principally in asthma and AD, guides the development of drugs
interacting with histamine (157–162), beta-adrenergic (163), muscarinic (164), neuropeptide Y
(NPY) (165), proton-sensing (166), chemokine (167), PG D₂ (168), and adenosine receptors (169),
among others (130). Despite the relatively large number of available compounds, few of them were
advanced to late-phase clinical investigation, and even fewer reached the market.

The H₄ receptor is found primarily on immune and inflammatory cells and is thus consid-
ered to contribute to the immunomodulatory actions of histamine (157). H₄ receptor-targeting
ligands were mainly developed to address H₁ antihistamine-unresponsive conditions, including
asthma and AD. Following success in preclinical studies, multiple selective H₄ receptor antag-
onists entered clinical trials. Results on the efficacy of UR-63325 in patients with AR have not
been reported, and in a Phase IIa clinical trial, toreforant (JNJ 38518168) failed to provide ther-
apeutic benefit in patients with uncontrolled persistent eosinophilic asthma (158). Similarly, the
benefits of fevipiprant, a nonsteroidal PGD₂ receptor 2 (DP₂) antagonist, were rather modest in
the clinical context (168).

AD remains an unmet medical need despite the recent insights (159), the expanding therapeutic pipeline (160) and the approval of biologics, such as dupilumab, for the management of moderate-to-severe disease (40). In patients with AD, H₁ antihistamines are used to manage pruritus, but there is insufficient evidence to recommend their general use (161). H₄ receptor blockade was suggested as a putative therapeutic target in Th2-polarized and Th17 inflammation. A first proof-of-concept study of the H₄ receptor antagonist JNJ 39758979 in patients with AD was prematurely discontinued due to its association with drug-induced agranulocytosis (170). Adriforant (ZPL389), another H₄ receptor antagonist, advanced to Phase II trials, but it did not meet the efficacy criteria and its development for AD was also discontinued (162).

New approaches to treat allergies have started to appreciate the complex neuroimmune com-
munication across allergic disorders. Beyond the bronchodilating action of β₂-adrenergic receptor
(β₂AR) agonists, ample evidence argues for the control of immune responses by adrenergic
signaling elicited mainly via βARs expressed in immune cells (163). Notably, the canonical cAMP-
mediated pathway is thought to be responsible for the potent bronchodilator effects of β₂ARs,
whereas activation of noncanonical β-arrestin-dependent signaling is implicated in the modula-
tion of airway eosinophilic inflammation (130). However, the clinical investigation of nadolol and
propranolol failed to clarify whether β-blockers could provide therapeutic benefits for patients
with asthma (130).

Besides catecholamines, NPY is released upon sympathetic stimulation in the lymph nodes. By acting on Y₁ receptors (Y₁R) expressed on various immune cells, such as B, T, and NK cells, macrophages, DCs, and MCs, NPY largely skews the airway response toward T2 immunity in mice (165). By interacting with Y₂R, NPY has been suggested to reduce histaminergic and IL-31-associated itch, an effect that could be exploited in the management of AD (171).

In addition, substantial advances have been made in dissecting the profile of the cholinergic modulation of allergic effector cells such as MCs, basophils, and Eos as well as of other key immune players, including DCs, Mφ, and ILC2. Acetylcholine derived from various cellular sources differentially regulates ALLINF by enhancing ILC2-driven eosinophilia and preventing neutrophilia (164, 172). Tiotropium, a long-acting antagonist mainly at the M3 muscarinic
acetylcholine receptors (mAchRs) that is commonly used as a bronchodilator, has been shown to attenuate ILC2-dependent T2 lung inflammation (173), whereas the effects of the M1/M3 mAchR antagonist glycopyrronium on sputum eosinophils following allergen challenge in asthmatics are currently being investigated in a Phase III clinical trial (NCT04259164).

Furthermore, deciphering the significance of immunometabolism in ALLINF is expected to provide new targets for drug development. Acidification of inflamed tissues is driven by the high glycolytic activity and the consequent accumulation of lactic acid. The low extracellular pH-sensing G protein-coupled receptor 65 (GPR65) is expressed in different immune cell types, including granulocytes and lymphocytes (166). Evidence derived from in vitro experiments, animal models, and human studies suggests that GPR65 differentially regulates Eo and MC viability and accumulation in inflamed environments and implicates this GPCR in food allergies, AD, and asthma (166).

## CONCLUSION AND PERSPECTIVES

Scientific, biotechnological, and clinical approaches over the past decades have uncovered diverse immune components that play significant roles in the pathophysiologic complexity of ALLINF and hypersensitivity reactions, thereby offering new immunopharmacological targets. This allows for the development and exploitation of innovative patient-oriented immunomodulatory tools focused on difficult-to-manage allergic conditions, yet without disregarding old players in approved and investigational therapeutic interventions. For example, MC-derived mediators exemplified by histamine and arachidonic acid-derived products, or their target cells, have long been addressed by agents such as glucocorticoids and $H_1$ antihistamines. Interestingly, ALLINF players also contribute to immune surveillance and continue to provide effective targets that are exploited by the modern approaches of precision and personalized pharmacotherapy.

As illustrated in **Table 1**, the armamentarium of novel immunopharmacological medicines to treat allergic diseases comprises biologics that target IgE, cytokines, and cytokine receptors as well as small-molecule inhibitors of signal transduction in pivotal immune cells that shape ALLINF. In addition, several new targets are currently being tested in clinical studies of allergic diseases. Promising investigational immunomodulating drugs likely to play an important role in therapeutic regimens for allergies in the near future include mAbs attenuating Th17 skewing or restoring T cell homeostasis via mitigation of the interaction between the checkpoints OX40 and OX40L, whereas modification of the key role played by Btk in B cell differentiation and MC activation is targeted by new small-molecule Btk inhibitors (**Table 2**). Furthermore, ongoing research in ALLINF aims to characterize diagnostic and prognostic biomarkers and identify disease phenotypes, endotypes, severity, and activity susceptible to specific treatment for critical unmet clinical needs in allergic diseases.

## SUMMARY POINTS

1. Allergic diseases are chronic, noncommunicable diseases that are highly prevalent in populations with a Westernized lifestyle. Allergy is defined as an adaptive immune response toward an antigen, denoted as an allergen, which can be inhaled, ingested, injected, or applied on a mucocutaneous surface.

2. Most allergic reactions present as immediate hypersensitivity reactions due to immunoglobulin E (IgE)-mediated activation of mast cells, followed by a complex type 2 immune reaction involving the interleukins IL-4 and IL-13 as hallmark cytokines and eosinophils and T and B lymphocytes as prominent players.
3. The early phase, characterized by mast cell mediator release, such as histamine and tryptase, is followed by a late phase of inflammation and in some cases by a chronic inflammatory phase, which leads to tissue remodeling and functional impairment. Allergic asthma, allergic rhinitis and rhinoconjunctivitis, food allergy, drug allergy, insect venom allergy, and IgE-mediated anaphylaxis are typical examples of allergic conditions.

4. The traditional therapeutic armamentarium addressing allergic diseases comprises drugs that provide symptomatic relief, such as H₁ antihistamines and glucocorticoids.

5. The advent of therapeutic monoclonal antibodies (mAbs) targeting players of the allergic inflammation has allowed for more efficient management of patients with severe or uncontrolled presentations, mainly in asthma and atopic dermatitis.

6. Notable examples of antiallergic therapeutic biologics currently in use are the anti-IgE mAbs omalizumab and ligelizumab; dupilumab [which binds the α subunit of the IL-4 receptor (IL-4Rα) shared by IL-4 and IL-13 receptors]; the anti-IL-13 mAb tralokinumab; the mAbs mepolizumab, reslizumab, and benralizumab, which target the IL-5 receptor; and tezepelumab, which binds to the alarmin thymic stromal lymphopoietin (TSLP) released from epithelial cells.

7. Novel therapeutic interventions used mainly for atopic dermatitis include the small-molecule drugs targeting Janus kinase (JAK) signaling such as upadacitinib, abrocitinib, and baricitinib.

8. Promising investigational immunomodulatory drugs likely to play an important therapeutic role in the near future include mAbs that attenuate Th17 skewing or inhibit OX40-OX40L checkpoint interaction and new small-molecule Bruton's tyrosine kinase (Btk) inhibitors.

## FUTURE ISSUES

1. The newly characterized Mas-related G protein coupled receptor (MRGPRX2) and sialic acid-binding Ig-like lectin (Siglec)-8 may provide new therapeutic targets.

2. Mast cell-derived resolvins will pave the way to targeting functional restoration beyond allergic inflammation and tissue remodeling.

3. Immunopharmacological research may focus on improved individual molecules and on potential benefits of combining available therapeutic tools with nonredundant targets.

4. The molecular dissection of elusive mechanisms underlying resistant disease phenotypes, such as neutrophilic inflammation, is expected to allow the identification of novel therapeutic targets.

5. Characterization of pathway-specific biomarkers that are able to recapitulate disease phenotypes and endotypes for the choice and follow-up selection of novel therapeutic tools is a priority for future immunopharmacological research.

## DISCLOSURE STATEMENT

J.V. reports speaker and consultancy fees and travel support in the past five years from ALK, AstraZeneca, HpVac, Novartis, L'Oréal, Sanofi, Stallergenes Greer, Thermo Fisher Scientific, outside the submitted work. F.L.-S. reports consultancy fees during the past year from HI-Bio.
ACKNOWLEDGMENTS

E.T. has served as Jacob and Lena Joels Memorial Foundation Visiting Professor, and J.V. is a recipient of the Marie and Matthew Heller Visiting Professor fellowship, both from the Hebrew University of Jerusalem, Jerusalem, Israel.

This research has been funded by grants from the United States–Israel Binational Science Foundation (2015045), Israel Science Foundation (343/22), Rosetrees Trust (UK), Aimwell Charitable Trust (UK), and the Emalie Gutterman Memorial Endowment Fund (USA). It has also benefited from the support of the European Histamine Research Society (https://www.ehrs.org.uk/) and that of the European Mast Cell and Basophil Research Network (https://embrn.eu/).

The authors thank Ms. Madelyn Segev for careful proofreading of the manuscript.

LITERATURE CITED

1. Celebi Sozener Z, Ozdel Ozturk B, Cerci P, Turk M, Gorgulu Akin B, et al. 2022. Epithelial barrier hypothesis: effect of the external exposome on the microbiome and epithelial barriers in allergic disease. *Allergy* 77:1418–49

2. GBD 2019 Dis. Inj. Collab. 2020. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. *Lancet* 396:1204–22

3. Tanno LK, Demoly P. 2022. Allergy in the World Health Organization's International Classification of Diseases (ICD)-11. *Pediatr. Allergy Immunol.* 33(Suppl. 27):5–7

4. Gieseck RL 3rd, Wilson MS, Wynn TA. 2018. Type 2 immunity in tissue repair and fibrosis. *Nat. Rev. Immunol.* 18:62–76

5. Blank U, Huang H, Kawakami T. 2021. The high affinity IgE receptor: a signaling update. *Curr. Opin. Immunol.* 72:51–58

6. Levi-Schaffer F, Gibbs BF, Hallgren J, Pucillo C, Redegeld F, et al. 2022. Selected recent advances in understanding the role of human mast cells in health and disease. *J. Allergy Clin. Immunol.* 149:1833–44

7. Akdis CA, Arkwright PD, Bruggen MC, Busse W, Gadina M, et al. 2020. Type 2 immunity in the skin and lungs. *Allergy* 75:1582–605

8. Gazzinelli-Guimaraes PH, Nutman TB. 2018. Helminth parasites and immune regulation. *F1000Res* 7:1685

9. Custovic A, Henderson J, Simpson A. 2019. Does understanding endotypes translate to better asthma management options for all? *J. Allergy Clin. Immunol.* 144:25–33

10. Maggi E, Parronchi P, Azzarone BG, Moretta L. 2022. A pathogenic integrated view explaining the different endotypes of asthma and allergic disorders. *Allergy* 77:3267–92

11. Treudler R, Simon JC. 2023. Developments and perspectives in allergology. *J. Dtsch. Dermatol. Ges.* 21:399–403

12. Molofsky AB, Locksley RM. 2023. The ins and outs of innate and adaptive type 2 immunity. *Immunity* 56:704–22

13. Landolina N, Levi-Schaffer F. 2016. Monoclonal antibodies: the new magic bullets for allergy: IUPHAR review 17. *Br. J. Pharmacol.* 173:793–803

14. Nakashima C, Yanagihara S, Otsuka A. 2022. Innovation in the treatment of atopic dermatitis: emerging topical and oral Janus kinase inhibitors. *Allergol. Int.* 71:40–46

15. Karra L, Haworth O, Priluck R, Levy BD, Levi-Schaffer F. 2015. Lipoxin B₄ promotes the resolution of allergic inflammation in the upper and lower airways of mice. *Mucosal Immunol.* 8:852–62

16. Puzzovio PG, Pahima H, George T, Mankuta D, Eliashar R, et al. 2023. Mast cells contribute to the resolution of allergic inflammation by releasing resolvin D1. *Pharmacol. Res.* 189:106691

17. Durham SR, Shamji MH. 2023. Allergen immunotherapy: past, present and future. *Nat. Rev. Immunol.* 23:317–28

18. Soh WT, Zhang J, Hollenberg MD, Vliagoftis H, Rothenberg ME, et al. 2023. Protease allergens as initiators-regulators of allergic inflammation. *Allergy* 78:1148–68
19. Chevigne A, Jacquet A. 2018. Emerging roles of the protease allergen Der p 1 in house dust mite-induced airway inflammation. *J. Allergy Clin. Immunol.* 142:398–400

20. Hellings PW, Steelant B. 2020. Epithelial barriers in allergy and asthma. *J. Allergy Clin. Immunol.* 145:1499–509

21. Irvine AD, McLean WH, Leung DY. 2011. Filaggrin mutations associated with skin and allergic diseases. *N. Engl. J. Med.* 365:1315–27

22. Castillo EF, Zheng H, Yang XO. 2018. Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation. *Cytokine Growth Factor Rev.* 39:19–25

23. de Kleer IM, Kool M, de Bruijn MJ, Willart M, van Moorleghem J, et al. 2016. Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. *Immunity* 45:1285–98

24. Cook EB, Stahl JL, Schwantes EA, Fox KE, Mathur SK. 2012. IL-3 and TNFα increase Thymic Stromal Lymphopoietin Receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation. *Clin. Mol. Allergy* 10:8

25. Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. 2013. The biology of thymic stromal lymphopoietin (TSLP). *Adv. Pharmacol.* 66:129–55

26. Marone G, Spadaro G, Braile M, Poto R, Criscuolo G, et al. 2019. Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma. *Expert Opin. Investig. Drugs* 28:931–40

27. Menzies-Gow A, Steenkamp J, Singh S, Erhardt W, Rowell J, et al. 2022. Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison. *J. Med. Econ.* 25:679–90

28. Hinks TSC, Levine SJ, Brusselle GG. 2021. Treatment options in type-2 low asthma. *Eur. Respir. J.* 57:2000528

29. Chow TG, Gill MA. 2020. Regulation of allergic inflammation by dendritic cells. *Curr. Opin. Allergy Clin. Immunol.* 20:56–63

30. Hilligan KL, Ronchese F. 2020. Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses. *Cell Mol. Immunol.* 17:587–99

31. Mirchandani AS, Besnard AG, Yip E, Scott C, Bain CC, et al. 2014. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. *J. Immunol.* 192:2442–48

32. Furue M, Furue M. 2021. OX40L-OX40 signaling in atopic dermatitis. *J. Clin. Med.* 10:2578

33. Guttman-Yassky E, Pavel AB, Zhou L, Estrada YD, Zhang N, et al. 2019. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. *J. Allergy Clin. Immunol.* 144:482–93.e7

34. Leyva-Castillo JM, Das M, Artru E, Yoon J, Galand C, Geha RS. 2021. Mast cell-derived IL-13 down-regulates IL-12 production by skin dendritic cells to inhibit the $T_{H1}$ cell response to cutaneous antigen exposure. *J. Allergy Clin. Immunol.* 147:2305–15.e3

35. Theoharides TC, Conti P. 2021. Mast cells to dendritic cells: Let IL-13 shut your IL-12 down. *J. Allergy Clin. Immunol.* 147:2073–74

36. Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, et al. 2004. Conditional deletion of *Gata3* shows its essential function in $T_{H1}-T_{H2}$ responses. *Nat. Immunol.* 5:1157–65

37. Walker JA, McKenzie ANJ. 2018. $T_{H2}$ cell development and function. *Nat. Rev. Immunol.* 18:121–33

38. Butcher MJ, Zhu J. 2021. Recent advances in understanding the Th1/Th2 effector choice. *Fac. Rev.* 10:30

39. Yamane H, Zhu J, Paul WE. 2005. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. *J. Exp. Med.* 202:793–804

40. Guttman-Yassky E, Bissonnette R, Ungar B, Suarez-Farinas M, Ardeleanu M, et al. 2019. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. *J. Allergy Clin. Immunol.* 143:155–72

41. Popovic B, Breed J, Rees DG, Gardener MJ, Vinall LM, et al. 2017. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. *J. Mol. Biol.* 429:208–19

42. Blair HA. 2022. Tralokinumab in atopic dermatitis: a profile of its use. *Clin. Drug. Investig.* 42:365–74

43. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. 2006. IL-13 signaling through the IL-13Rα2 receptor is involved in induction of TGF-β1 production and fibrosis. *Nat. Med.* 12:99–106
44. Moyle M, Cevikbas F, Harden JL, Guttman-Yassky E. 2019. Understanding the immune landscape in atopic dermatitis: the era of biologics and emerging therapeutic approaches. *Exp. Dermatol.* 28:756–68

45. Labib A, Ju T, Yosipovitch G. 2022. Managing atopic dermatitis with lebrikizumab—the evidence to date. *Clin. Cosmet. Investig. Dermatol.* 15:1065–72

46. Ridolo E, Incorvaia C, Pucciarini F, Makri E, Paoletti G, Canonica GW. 2022. Current treatment strategies for seasonal allergic rhinitis: Where are we heading? *Clin. Mol. Allergy* 20:9

47. Nogueira M, Torres T. 2021. Janus kinase inhibitors for the treatment of atopic dermatitis: focus on abrocitinib, baricitinib, and upadacitinib. *Dermatol. Pract. Concept.* 11:e2021145

48. Le M, Berman-Rosa M, Ghazawi FM, Bourcier M, Fiorillo L, et al. 2021. Systematic review on the efficacy and safety of oral Janus kinase inhibitors for the treatment of atopic dermatitis. *Front. Med.* 8:682547

49. Allen CDC. 2022. Features of B cell responses relevant to allergic disease. *J. Immunol.* 208:257–66

50. Gowthaman U, Sikder S, Lee D, Fisher C. 2022. T follicular helper cells in IgE-mediated pathologies. *Curr. Opin. Immunol.* 74:133–39

51. Mitre E, Nutman TB. 2006. IgE memory: persistence of antigen-specific IgE responses years after treatment of human filarial infections. *J. Allergy Clin. Immunol.* 117:939–45

52. Eckl-Dorna J, Villazala-Merino S, Campion NJ, Byazrova M, Filatov A, et al. 2019. Tracing IgE-producing cells in allergic patients. *Cells* 8:994

53. McDonnell JM, Dhaliwal B, Sutton BJ, Gould HJ. 2023. IgE, IgE receptors and anti-IgE biologics: protein structures and mechanisms of action. *Annu. Rev. Immunol.* 41:255–75

54. Yamaguchi M, Lantz CS, Oettgen HC, Katona IM, Fleming T, et al. 1997. IgE enhances mouse mast cell FcεRI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. *J. Exp. Med.* 185:663–72

55. Yamaguchi M, Sayama K, Yano K, Lantz CS, Noben-Trauth N, et al. 1999. IgE enhances Fc epsilon receptor I expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood-derived mast cells: synergistic effect of IL-4 and IgE on human mast cell Fcε receptor I expression and mediator release. *J. Immunol.* 162:5455–65

56. Jensen RK, Plum M, Tjerrild L, Jakob T, Spillner E, Andersen GR. 2015. Structure of the omalizumab Fab. *Acta Crystallogr. F Struct. Biol. Commun.* 71:419–26

57. Holgate S, Smith N, Massanari M, Jimenez P. 2009. Effects of omalizumab on markers of inflammation in patients with allergic asthma. *Allergy* 64:1728–36

58. Bousquet J, Humbert M, Gibson PG, Kostikas K, Jaumont X, et al. 2021. Real-world effectiveness of omalizumab in severe allergic asthma: a meta-analysis of observational studies. *J. Allergy Clin. Immunol. Pract.* 9:2702–14

59. Agache I, Rocha C, Pereira A, Song Y, Alonso-Coello P, et al. 2021. Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: a systematic review for the EAACI Biologicals Guidelines. *Allergy* 76:59–70

60. Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, et al. 2022. The international EAACI/GA²LEN/EuroGuiDerm/APAACI guideline for the definition, classification, diagnosis, and management of urticaria. *Allergy* 77:734–66

61. Chong LY, Piromchai P, Sharp S, Snidvongs K, Webster KE, et al. 2021. Biologics for chronic rhinosinusitis. *Cochrane Database Syst. Rev.* 3:CD013513

62. Tsabouri S, Ntritsos G, Koskeridis F, Evangelou E, Olsson P, Kostikas K. 2021. Omalizumab for the treatment of allergic rhinitis: a systematic review and meta-analysis. *Rhinology* 59:501–10

63. Chia SL, Kapoor S, Carvalho C, Bajenoff M, Gentek R. 2023. Mast cell ontogeny: from fetal development to life-long health and disease. *Immunol. Rev.* 315:31–53

64. Nilsson G, Butterfield JH, Nilsson K, Siegbahn A. 1994. Stem cell factor is a chemotactic factor for human mast cells. *J. Immunol.* 153:3717–23

65. Tsai M, Valent P, Galli SJ. 2022. KIT as a master regulator of the mast cell lineage. *J. Allergy Clin. Immunol.* 149:1845–54

66. Miralda I, Samanas NB, Seo AJ, Foronda JS, Sachen J, et al. 2023. Siglec-9 is an inhibitory receptor on human mast cells in vitro. *J. Allergy Clin. Immunol.* 152(3):711–24
67. Varricchi G, Rossi FW, Galdiero MR, Granata F, Criscuolo G, et al. 2019. Physiological roles of mast cells: Collegium Internationale Allergologicum update 2019. *Int. Arch. Allergy Immunol.* 179:247–61

68. Frossi B, Mion F, Tripodo C, Colombo MP, Pucillo CE. 2017. Rheostatic functions of mast cells in the control of innate and adaptive immune responses. *Trends Immunol.* 38:648–56

69. Starkl P, Watzenboeck ML, Popov LM, Zahalka S, Hladik A, et al. 2020. IgE effector mechanisms, in concert with mast cells, contribute to acquired host defense against *Staphylococcus aureus*. *Immunity* 53:793–804.e9

70. Dudeck J, Kotrba J, Immler R, Hoffmann A, Voss M, et al. 2021. Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation. *Immunity* 54:468–83.e5

71. Varricchi G, Marone G, Kovanen PT. 2020. Cardiac mast cells: underappreciated immune cells in cardiovascular homeostasis and disease. *Trends Immunol.* 41:734–46

72. Tiligada E, Ennis M. 2020. Histamine pharmacology: from Sir Henry Dale to the 21st century. *Br. J. Pharmacol.* 177:469–89

73. Simons FE. 2004. Advances in H1-antihistamines. *N. Engl. J. Med.* 351:2203–17

74. Panula P, Chazot PL, Cowart M, Gutzmer R, Leurs R, et al. 2015. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine receptors. *Pharmacol. Rev.* 67:601–55

75. Kyriakidis K, Zampeli E, Palaiologou M, Tiniakos D, Tiligada E. 2015. Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo. *Inflammation* 38:949–58

76. Hellman L, Akula S, Fu Z, Wernersson S. 2022. Mast cell and basophil granule proteases—in vivo targets and function. *Front. Immunol.* 13:918305

77. Michel M, Klingebiel C, Vitte J. 2023. Tryptase in type I hypersensitivity. *Ann. Allergy Asthma Immunol.* 130:169–77

78. Xue L, Salimi M, Panse I, Mjosberg JM, McKenzie AN, et al. 2014. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on T_H2 cells. *J. Allergy Clin. Immunol.* 133:1184–94

79. Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH. 2013. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates T_H2 cytokine production. *J. Allergy Clin. Immunol.* 132:205–13

80. Bulfone-Paus S, Nilsson G, Draber P, Blank U, Levi-Schaffer F. 2017. Positive and negative signals in mast cell activation. *Trends Immunol.* 38:657–67

81. Kolkhir P, Elieh-Ali-Komi D, Metz M, Siebenhaar F, Maurer M. 2022. Understanding human mast cells: lesson from therapies for allergic and non-allergic diseases. *Nat. Rev. Immunol.* 22:294–308

82. Suresh RV, Dunnam C, Vaidya D, Wood RA, Bochner BS, et al. 2023. Bruton's tyrosine kinase inhibition for the prevention of anaphylaxis: an open-label, phase 2 trial. Res. Sq. 2757218. https://doi.org/10.21203/rs.3.rs-2757218/v1

83. Mendes-Bastos P, Brasileiro A, Kolkhir P, Frischbutter S, Scheffel J, et al. 2022. Bruton's tyrosine kinase inhibition—an emerging therapeutic strategy in immune-mediated dermatological conditions. *Allergy* 77:2355–66

84. McLeod JJ, Baker B, Ryan JJ. 2015. Mast cell production and response to IL-4 and IL-13. *Cytokine* 75:57–61

85. Church MK. 2017. Allergy, histamine and antihistamines. In *Histamine and Histamine Receptors in Health and Disease*, ed. Y Hattori, R Seifert, pp. 321–31. Cham, Switz.: Springer

86. Kawauchi H, Yanai K, Wang DY, Itahashi K, Okubo K. 2019. Antihistamines for allergic rhinitis treatment from the viewpoint of nonsedative properties. *Int. J. Mol. Sci.* 20:213

87. Castillo M, Scott NW, Mustafa MZ, Mustafa MS, Azuara-Blanco A. 2015. Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis. *Cochrane Database Syst. Rev.* 6:CD009566

88. Wise SK, Damask C, Greenhawt M, Oppenheimer J, Roland LT, et al. 2023. A synopsis of guidance for allergic rhinitis diagnosis and management from ICAR 2023. *J. Allergy Clin. Immunol. Pract.* 11:773–96

89. Harvima IT, Levi-Schaffer F, Draber P, Friedman S, Polakovicova I, et al. 2014. Molecular targets on mast cells and basophils for novel therapies. *J. Allergy Clin. Immunol.* 134:530–44
90. Wood RA, Chinthrajah RS, Eggel A, Bottoli I, Gautier A, et al. 2022. The rationale for development of ligelizumab in food allergy. *World Allergy Organ*. *J*. 15:100690

91. Dispenza MC, Metcalfe DD, Olivera A. 2023. Research advances in mast cell biology and their translation into novel therapies for anaphylaxis. *J. Allergy Clin. Immunol. Pract*. 11:2032–42

92. Mori Y, Iwasaki H, Kohno K, Yoshimoto G, Kikushige Y, et al. 2009. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. *J. Exp. Med*. 206:183–93

93. Robida PA, Puzzovio PG, Pahima H, Levi-Schaffer F, Bochner BS. 2018. Human eosinophils and mast cells: birds of a feather flock together. *Immunol. Rev*. 282:151–67

94. Farahi N, Singh NR, Heard S, Loutsios C, Summers C, et al. 2012. Use of 111-indium-labeled autologous eosinophils to establish the in vivo kinetics of human eosinophils in healthy subjects. *Blood* 120:4068–71

95. Klion AD, Ackerman SJ, Bochner BS. 2020. Contributions of eosinophils to human health and disease. *Annu. Rev. Pathol*. 15:179–209

96. Acharya KR, Ackerman SJ. 2014. Eosinophil granule proteins: form and function. *J. Biol. Chem*. 289:17406–15

97. Grozdanovic MM, Doyle CB, Liu L, Maybruck BT, Kwatia MA, et al. 2020. Charcot-Leyden crystal protein/galectin-10 interacts with cationic ribonucleases and is required for eosinophil granulogenesis. *J. Allergy Clin. Immunol*. 146:377–89.e10

98. Lombardi C, Berti A, Cottini M. 2022. The emerging roles of eosinophils: implications for the targeted treatment of eosinophilic-associated inflammatory conditions. *Curr. Res. Immunol*. 3:42–53

99. Galdiero MR, Varricchi G, Seaf M, Marone G, Levi-Schaffer F, Marone G. 2017. Bidirectional mast cell-eosinophil interactions in inflammatory disorders and cancer. *Front. Med*. 4:103

100. Adachi T, Alam R. 1998. The mechanism of IL-5 signal transduction. *Am. J. Physiol*. 275:C623–33

101. Gevaert P, Hellman C, Lundblad L, Lundahl J, Holtappels G, et al. 2009. Differential expression of the interleukin 5 receptor α isoforms in blood and tissue eosinophils of nasal polyp patients. *Allergy* 64:725–32

102. Heaney LG, Perez de Llano L, Al-Ahmad M, Backer V, Busby J, et al. 2021. Eosinophilic and noneosinophilic asthma: an expert consensus framework to characterize phenotypes in a global real-life severe asthma cohort. *Chest* 160:814–30

103. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, et al. 2012. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. *Lancet* 380:651–59

104. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, et al. 2014. Mepolizumab treatment in patients with severe eosinophilic asthma. *N. Engl. J. Med*. 371:1198–207

105. Nagase H, Suzukawa M, Oishi K, Matsunaga K. 2023. Biologics for severe asthma: the real-world evidence, effectiveness of switching, and prediction factors for the efficacy. *Allergol. Int*. 72:11–23

106. Deeks ED, Brusselle G. 2017. Reslizumab in eosinophilic asthma: a review. *Drugs* 77:777–84

107. Van Hulst G, Jorssen J, Jacobs N, Henket M, Louis R, et al. 2022. Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma. *Eur. Respir. J*. 59:2100935

108. Davila Gonzalez I, Moreno Benitez F, Quirce S. 2019. Benralizumab: a new approach for the treatment of severe eosinophilic asthma. *J. Investig. Allergol. Clin. Immunol*. 29:84–93

109. Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, et al. 2010. MEDI-563, a humanized anti-IL-5 receptor α mAb with enhanced antibody-dependent cell-mediated cytotoxicity function. *J. Allergy Clin. Immunol*. 125:1344–53.e2

110. Pease JE, Williams TJ. 2001. Eotaxin and asthma. *Curr. Opin. Pharmacol*. 1:248–53

111. Salib RJ, Lau LC, Howarth PH. 2005. Nasal lavage fluid concentrations of eotaxin-1 (CCL11) in naturally occurring allergic rhinitis: relationship to disease activity, nasal luminal eosinophil influx, and plasma protein exudation. *Clin. Exp. Allergy* 35:995–1002

112. Hoffmann HJ, Nielsen LP, Harving H, Heinig JH, Dahl R. 2008. Asthmatics able to step down from inhaled corticosteroid treatment without loss of asthma control have low serum eotaxin/CCL11. *Clin. Respir. J*. 2:149–57

113. Minai-Fleminger Y, Elishmereni M, Vita F, Soranzo MR, Mankuta D, et al. 2010. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. *Cell Tissue Res*. 341:405–15
114. Gangwar RS, Landolina N, Arpinati L, Levi-Schaffer F. 2017. Mast cell and eosinophil surface receptors as targets for anti-allergic therapy. *Pharmacol. Ther.* 170:37–63

115. Munitz A, Bachelet I, Fraenkel S, Katz G, Mandelboim O, et al. 2005. 2B4 (CD244) is expressed and functional on human eosinophils. *J. Immunol.* 174:110–18

116. Gangwar RS, Minai-Fleminger Y, Seaf M, Gutgold A, Shikotra A, et al. 2017. CD48 on blood leukocytes and in serum of asthma patients varies with severity. *Allergy* 72:888–95

117. Zoabi Y, Rahimli Alekberli F, Minai-Fleminger Y, Eliashar R, Levi-Schaffer F. 2021. CD48 expression on eosinophils in nasal polyps of chronic rhinosinusitis patients. *Int. Arch. Allergy Immunol.* 182:962–70

118. Minai-Fleminger Y, Gangwar RS, Migalovich-Sheikhet H, Seaf M, Leibovici V, et al. 2014. The CD48 receptor mediates *Staphylococcus aureus* human and murine eosinophil activation. *Clin. Exp. Allergy* 44:1335–46

119. Bachelet I, Munitz A, Berent-Maoz B, Mankuta D, Levi-Schaffer F. 2008. Suppression of normal and malignant Kit signaling by a bispecific antibody linking kit with CD300a. *J. Immunol.* 180:6064–69

120. Bachelet I, Munitz A, Levi-Schaffer F. 2006. Abrogation of allergic reactions by a bispecific antibody fragment linking IgE to CD300a. *J. Allergy Clin. Immunol.* 117:1314–20

121. Landolina N, Zaffran I, Smiljkovic D, Serrano-Candelas E, Schmiedel D, et al. 2020. Activation of Siglec-7 results in inhibition of in vitro and in vivo growth of human mast cell leukemia cells. *Pharmacol. Res.* 158:104682

122. Legrand F, Landolina N, Zaffran I, Emeh RO, Chen E, et al. 2019. Siglec-7 on peripheral blood eosinophils: surface expression and function. *Allergy* 74:1257–65

123. Mizrahi S, Gibbs BF, Karra L, Ben-Zimra M, Levi-Schaffer F. 2014. Siglec-7 is an inhibitory receptor on human mast cells and basophils. *J. Allergy Clin. Immunol.* 134:230–33

124. Williams DM. 2018. Clinical pharmacology of corticosteroids. *Respir. Care* 63:655–70

125. Li H, Zuo J, Tang W. 2018. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. *Front. Pharmacol.* 9:1048

126. Chinn AM, Salmeron C, Lee J, Sriram K, Raz E, Insel PA. 2022. PDE4B is a homeostatic regulator of cyclic AMP in dendritic cells. *Front. Pharmacol.* 13:833832

127. Chinn AM, Insel PA. 2020. Cyclic AMP in dendritic cells: a novel potential target for disease-modifying agents in asthma and other allergic disorders. *Br. J. Pharmacol.* 177:3363–77

128. Agnihotri G, Lio PA. 2020. Revisiting therapies for atopic dermatitis that failed clinical trials. *Clin. Drug Investig.* 40:421–31

129. Goonathilake MR, Waqar S, George S, Jean-Baptiste W, Yusuf Ali A, et al. 2022. Can phosphodiesterase 4 inhibitor therapy be used in respiratory diseases other than chronic obstructive pulmonary disease? *Cureus* 14:e27132

130. Wendell SG, Fan H, Zhang C. 2020. G protein-coupled receptors in asthma therapy: pharmacology and drug action. *Pharmacol. Rev.* 72:1–49

131. Coruzzi G, Pozzoli C, Adami M, Grandi D, Guido N, et al. 2012. Strain-dependent effects of the histamine H4 receptor antagonist JNJ777120 in a murine model of acute skin inflammation. *Exp. Dermatol.* 21:32–37

132. Aun MV, Bonamichi-Santos R, Arantes-Costa FM, Kalil J, Giavina-Bianchi P. 2017. Animal models of asthma: utility and limitations. *J. Asthma Allergy* 10:293–301

133. Siebenhaar F, Falcone FH, Tiligada E, Hammel I, Maurer M, et al. 2015. The search for mast cell and basophil models—Are we getting closer to pathophysiological relevance? *Allergy* 70:1–5

134. Chan R, Kuo CRW, Lipworth B. 2020. Pragmatic clinical perspective on biologics for severe refractory type 2 asthma. *J. Allergy Clin. Immunol. Pract.* 8:3363–70

135. Kandi V, Vadakedath S. 2023. Clinical trials and clinical research: a comprehensive review. *Cureus* 15:e35077

136. Kruse RL, Vanijcharoenkarn K. 2018. Drug repurposing to treat asthma and allergic disorders: progress and prospects. *Allergy* 73:313–22

137. Facheris P, Jeffery J, Del Duca E, Guttman-Yassky E. 2023. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. *Cell Mol. Immunol.* 20:448–74

138. Kyriakopoulos C, Gogali A, Bartziokas K, Kostikas K. 2021. Identification and treatment of T2-low asthma in the era of biologics. *ERJ Open Res.* 7:00309-2020
139. Suárez-Fariñas M, Dhingra N, Gittler J, Shemer A, Cardinale I, et al. 2013. Intrinsic atopic dermatitis shows similar $T_H_2$ and higher $T_H_{17}$ immune activation compared with extrinsic atopic dermatitis. *J. Allergy Clin. Immunol.* 132:361–70

140. Ungar B, Pavel AB, Li R, Kimmel G, Nia J, et al. 2021. Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis. *J. Allergy Clin. Immunol.* 147:394–97

141. Tyring SK, Rich P, Tada Y, Beeck S, Messina I, et al. 2023. Risankizumab in patients with moderate-to-severe atopic dermatitis: a Phase 2, randomized, double-blind, placebo-controlled study. *Dermatol. Ther.* 13:595–608

142. Kelsen SG, Agache IO, Soong W, Israel E, Chupp GL, et al. 2021. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial. *J. Allergy Clin. Immunol.* 148:790–98

143. Chan R, Stewart K, Misirovs R, Lipworth BJ. 2022. Targeting downstream type 2 cytokines or upstream epithelial alarmins for severe asthma. *J. Allergy Clin. Immunol. Pract.* 10:1497–505

144. Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, Igawa K, et al. 2023. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. *Lancet* 401:204–14

145. Helou DG, Shafiei-Jahani P, Lo R, Howard E, Hurrell BP, et al. 2020. PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity. *Nat. Commun.* 11:3998

146. Helou DG, Shafiei-Jahani P, Hurrell BP, Painter JD, Quach C, et al. 2022. LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity. *J. Allergy Clin. Immunol.* 149:223–36.e6

147. Schanin J, Korver W, Brock EC, Leung J, Benet Z, et al. 2022. Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells. *Commun. Biol.* 5:1226

148. Bachelet I, Munitz A, Moretta A, Moretta L, Levi-Schaffer F. 2005. The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells. *J. Immunol.* 175:7989–95

149. Munitz A, Bachelet I, Levi-Schaffer F. 2006. Reversal of airway inflammation and remodeling in asthma by a bispecific antibody fragment linking CCR3 to CD300a. *J. Allergy Clin. Immunol.* 118:1082–89

150. Terhorst-Molawi D, Hawro T, Grekowitz E, Kiefer L, Merchant K, et al. 2023. Anti-KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria. *Allergy* 78:1269–79

151. Maun HR, Jackman JK, Choy DF, Loyet KM, Staton TL, et al. 2019. An allosteric anti-tryptase antibody for the treatment of mast cell-mediated severe asthma. *Cell* 179:417–31.e19

152. Rymut SM, Sukumaran S, Sperinde G, Bremer M, Galanter J, et al. 2022. Dose-dependent inactivation of airway tryptase with a novel dissociating anti-tryptase antibody (MTPS9579A) in healthy participants: a randomized trial. *Clin. Transl. Sci.* 15:451–63

153. Pfeifer N, Guerin T, Colley K, Yates W, Kaufman E, et al. 2021. Safety, pharmacokinetics, and pharmacodynamics of TD-8236, an inhaled pan-JAK inhibitor, following single- and multiple-ascending doses in healthy volunteers and mild asthmatics. *Eur. Respir. J.* 58(Suppl. 65):OA1195

154. Zhao Y, Zhang L, Ding Y, Tao X, Ji C, et al. 2021. Efficacy and safety of SHR0302, a highly selective Janus kinase 1 inhibitor, in patients with moderate to severe atopic dermatitis: a Phase II randomized clinical trial. *Am. J. Clin. Dermatol.* 22:877–89

155. Maurer M, Berger W, Gimenez-Arnau A, Hayama K, Jain V, et al. 2022. Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria. *J. Allergy Clin. Immunol.* 150:1498–506.e2

156. Carvallo A, Sanchez-Fernandez S, Morales-Palacios MP. 2023. Fenebrutinib and BTK inhibition: unveiling a new target for the treatment of chronic spontaneous urticaria. *Allergy* 78:603–5

157. Zampeli E, Tiligada E. 2009. The role of histamine $H_4$ receptor in immune and inflammatory disorders. *Br. J. Pharmacol.* 157:24–33

158. Kollmeier AP, Barnathan ES, O'Brien C, Chen B, Xia YK, et al. 2018. A Phase 2a study of toreforant, a histamine $H_4$ receptor antagonist, in eosinophilic asthma. *Ann. Allergy Asthma Immunol.* 121:568–74

159. Zuberbier T, Beck LA, Bedbrook A, de Bruin-Weller M, Bousquet J, et al. 2023. Developing integrated care pathways for atopic dermatitis-challenges and unmet needs. *Clin. Transl. Allergy* 13:e12236

160. Bieber T. 2022. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. *Nat. Rev. Drug. Discov.* 21:21–40
161. Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, et al. 2014. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. *J. Am. Acad. Dermatol.* 71:327–49

162. Uluckan O, Bruno S, Wang Y, Wack N, Wilzopolski J, et al. 2023. Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice. *Eur. J. Pharmacol.* 945:175533

163. Chhatar S, Lal G. 2021. Role of adrenergic receptor signalling in neuroimmune communication. *Curr. Res. Immunol.* 2:202–17

164. Roberts LB, Berkachy R, Wane M, Patel DF, Schnoeller C, et al. 2022. Differential regulation of allergic airway inflammation by acetylcholine. *Front. Immunol.* 13:893844

165. Oda N, Miyahara N, Taniguchi A, Morichika D, Senoo S, et al. 2019. Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation. *Am. J. Physiol. Lung Cell. Mol. Physiol.* 316:L407–17

166. de Souza Ferreira S, Bek MK, Tibbitt CA. 2023. pH sensing shapes immune cell function: the role of GPR65 and its implications for allergic disease. *Allergy* 78:2061–63

167. Castan L, Magnan A, Bouchaud G. 2017. Chemokine receptors in allergic diseases. *Allergy* 72:682–90

168. Jahangir A, Sattar SBA, Rafay Khan Niazi M, Muhammad M, Jahangir A, et al. 2022. Efficacy and safety of fevipiprant in asthma: a review and meta-analysis. *Cureus* 14:e24641

169. Garcia-Garcia L, Olle L, Martin M, Roca-Ferrer J, Munoz-Cano R. 2021. Adenosine signaling in mast cells and allergic diseases. *Int. J. Mol. Sci.* 22:5203

170. Murata Y, Song M, Kikuchi H, Hisamichi K, Xu XL, et al. 2015. Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H₄R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis. *J. Dermatol.* 42:129–39

171. Ma H, Gao T, Jakobsson JET, Weman HM, Xu B, et al. 2020. The neuropeptide Y Y₂ receptor is coexpressed with Nppb in primary afferent neurons and Y₂ activation reduces histaminergic and IL-31-induced itch. *J. Pharmacol. Exp. Ther.* 372:73–82

172. Thomas CM, Peebles RS Jr. 2022. Neural regulation of ILC2s in allergic airway inflammation. *Front Allergy* 3:1094259

173. Matsuyama T, Machida K, Motomura Y, Takagi K, Doutake Y, et al. 2021. Long-acting muscarinic antagonist regulates group 2 innate lymphoid cell-dependent airway eosinophilic inflammation. *Allergy* 76:2785–96