scholarly journals Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

2021 ◽  
Vol 22 (9) ◽  
pp. 4369
Author(s):  
Corrado Pelaia ◽  
Giulia Pelaia ◽  
Claudia Crimi ◽  
Angelantonio Maglio ◽  
Luca Gallelli ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Human Monoclonal Antibody ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Airway Epithelial ◽  
Airborne Pollutants ◽  
Group 2 ◽  
Efficacy Profile ◽  
Refractory Asthma

Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.

scholarly journals Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1108
Author(s):  
Corrado Pelaia ◽  
Giulia Pelaia ◽  
Federico Longhini ◽  
Claudia Crimi ◽  
Cecilia Calabrese ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Randomized Clinical Trials ◽  
Lymphoid Cells ◽  
Interleukin 33 ◽  
Airborne Pollutants ◽  
Group 2 ◽  
New Perspective ◽  
Interleukin 25 ◽  
Near Future

Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by airway epithelium and exert a prominent role in asthma pathobiology. In particular, several environmental factors such as allergens, cigarette smoking, airborne pollutants, and infectious agents trigger the release of alarmins, which in turn act as upstream activators of pro-inflammatory pathways underlying type 2 (T2-high) asthma. Indeed, alarmins directly activate group 2 innate lymphoid cells (ILC2), eosinophils, basophils, and mast cells and also stimulate dendritic cells to drive the commitment of naïve T helper (Th) cells towards the Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable targets for add-on therapies of severe asthma. Within this context, the fully human anti-TSLP monoclonal antibody tezepelumab has been evaluated in very promising randomized clinical trials. Tezepelumab and other anti-alarmins are thus likely to become, in the near future, valuable therapeutic options for the biological treatment of uncontrolled severe asthma.

scholarly journals Allergen protease-induced Gsdmd p40 controls IL-33 secretion

2021 ◽  
Author(s):  
Bing Sun ◽  
Bin Wu ◽  
Dong Wu ◽  
Feng Shao ◽  
Yaguang Zhang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Critical Role ◽  
Allergic Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Allergen Exposure ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Airway Epithelial ◽  
Group 2 ◽  
Inflammatory Caspases

Abstract Interleukin (IL)-33, an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammation, such as that in asthma. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we demonstrated that Gasdermin D (Gsdmd) functions as a conduit for IL-33 secretion following allergen protease exposure. Gsdmd was rapidly cleaved into a functional neo-form, the N-terminal p40 fragment (p40 NT-Gsdmd), in the murine airway epithelium when cells were exposed to allergen proteases from fungi, house dust mites (HDMs), or bacteria. This cleavage event that produces the p40 Gsdmd fragment was independent of inflammatory caspases-1/11, as it could not be inhibited by caspase-1 and caspase-11 deficiency in murine cells. The functional p40 NT-Gsdmd fragment directly contributed to the secretion of both the nuclear full-length form and cytosolic mature form of IL-33. Both Gsdmd deficiency and blockade of the generation of p40 by amino acid mutation or deletion of residues 308–313 (ELRQQ) in the Gsdmd sequence could efficiently prevent IL-33 release in airway epithelial cells. In mice, Gsdmd deficiency prevented IL-33 release and hindered the activation of group 2 innate lymphoid cells (ILC2s), thus alleviating airway inflammation and lung tissue damage after stimulation with HDMs or papain. Our findings uncovered a mechanism of Gsdmd-mediated IL-33 release under allergen exposure and offer insight into Gsdmd cleavage prevention as a potential approach to reduce allergic airway inflammation.

scholarly journals Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Charu Rajput ◽  
Mingyuan Han ◽  
Tomoko Ishikawa ◽  
Jing Lei ◽  
Adam M. Goldsmith ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Airway Epithelial ◽  
Eosinophilic Inflammation ◽  
Asthma Exacerbations ◽  
Rhinovirus C ◽  
Type 2 Inflammation

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.

Advances and Evolving Concepts in Allergic Asthma

2018 ◽  
Vol 39 (01) ◽  
pp. 064-081 ◽  
Author(s):  
Hui-Ying Tung ◽  
Evan Li ◽  
Cameron Landers ◽  
An Nguyen ◽  
Farrah Kheradmand ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Immunoglobulin E ◽  
Airway Remodeling ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Airway Epithelial ◽  
Clotting Factors ◽  
Particulate Pollution

AbstractAllergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E–secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting factors such as fibrinogen. Recent clinical trials have demonstrated that targeting inflammatory pathways orchestrated through IL-4, IL-5, IL-13, and the prostaglandin receptor CRTH2 is potentially highly effective in adult asthma.

scholarly journals Pulmonary neuroendocrine cells amplify allergic asthma responses

Science ◽  
2018 ◽  
Vol 360 (6393) ◽  
pp. eaan8546 ◽  
Author(s):  
Pengfei Sui ◽  
Darin L. Wiesner ◽  
Jinhao Xu ◽  
Yan Zhang ◽  
Jinwoo Lee ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Goblet Cell ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Neuroendocrine Cells ◽  
Airway Epithelial ◽  
Branch Points ◽  
Cell Hyperplasia ◽  
Pulmonary Neuroendocrine Cells ◽  
Group 2

Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.

scholarly journals Group 2 Innate Lymphoid Cells and the House Dust Mite-Induced Asthma Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1178
Author(s):  
Yuichiro Yasuda ◽  
Tatsuya Nagano ◽  
Kazuyuki Kobayashi ◽  
Yoshihiro Nishimura
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
House Dust ◽  
Innate Lymphoid Cells ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Airway Epithelial ◽  
Group 2 ◽  
Asthma Mouse Model

Asthma is an important issue not only in health but also in economics worldwide. Therefore, asthma animal models have been frequently used to understand the pathogenesis of asthma. Recently, in addition to acquired immunity, innate immunity has also been thought to be involved in asthma. Among innate immune cells, group 2 innate lymphoid cells (ILC2s) have been considered to be crucial for eosinophilic airway inflammation by releasing T helper 2 cytokines. Moreover, house dust mites (HDMs) belonging to group 1 act on airway epithelial cells not only as allergens but also as cysteine proteases. The production of interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP) from airway epithelial cells was induced by the protease activity of HDMs. These cytokines activate ILC2s, and activated ILC2s produce IL-5, IL-9, IL-13, and amphiregulin. Hence, the HDM-induced asthma mouse model greatly contributes to understanding asthma pathogenesis. In this review, we highlight the relationship between ILC2s and the HDM in the asthma mouse model to help researchers and clinicians not only choose a proper asthma mouse model but also to understand the molecular mechanisms underlying HDM-induced asthma.

scholarly journals Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis

2020 ◽  
Vol 32 (6) ◽  
pp. 407-419 ◽  
Author(s):  
Yurina Miyajima ◽  
Kafi N Ealey ◽  
Yasutaka Motomura ◽  
Miho Mochizuki ◽  
Natsuki Takeno ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Adipocyte Differentiation ◽  
Allergic Inflammation ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Brown Adipocytes ◽  
Morphogenetic Protein ◽  
Group 2

Abstract Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

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