scholarly journals Aerosol Biologics for the Treatment of Eosinophilic Asthma

2022 ◽  
Vol 3 (1) ◽  
pp. 01-05
Author(s):  
Nightingale Syabbalo
Keyword(s):  
Dry Powder Inhaler ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
Lymphoid Cells ◽  
Interleukin 4 ◽  
Controlled Clinical Trial ◽  
Fab Fragment ◽  
Eosinophilic Asthma ◽  
Asthmatic Response

Asthma is a heterogeneous chronic airway disease comprising of distinct phenotypes characterized by different immunopathophysiologic pathways, clinical features, disease severity, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed cellularity, and paucigranulocytic asthma. Eosinophilic asthma is principally a T helper type 2 (Th2)-mediated airway disease. However, several other immune and structural cells secrete the cytokines implicated in the pathogenesis of eosinophilic asthma. Innate type 2 lymphoid cells, mast cells, basophils, and eosinophils secrete Th2 cytokines, such as interleukin-4 (IL-4), IL-13, and IL-5. Additionally, airway epithelial cells produce alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Alarmins are the key initiators of allergic inflammation at the sentinel mucosal surfaces. Innovative biotherapeutic research has led to the discovery of monoclonal antibodies which target and inhibit the immunopathological effects of the cytokines involved in the pathogenesis of eosinophilic asthma. Parenteral biologics targeting the inciting interleukins, include mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα), dupilumab (anti-4Rα), and tezelizumab (anti-TSLP). They have been shown to significantly reduce annualized exacerbation rates, improve asthma control, lung function, and quality of life. Currently, there are no pulmonary delivered aerosol biologics for topical treatment of asthma. CSJ117 is a potent neutralizing antibody Fab fragment against TSLP, formulated as a PulmoSol TM engineered powder, and is delivered to the lungs by a dry powder inhaler. Phase 2 placebo-controlled clinical trial evaluated the efficacy and safety of CSJ117. CSJ117 delivered as an inhaler attenuated the late asthmatic response (LAR), and the early asthmatic response (EAR) after allergen inhalation challenge (AIC) at day 84 of treatment. The maximum decrease in FVE1 from pre-AIC were significantly lower in the CSJ117 group compared to placebo (P = 029), during LAR. CSJ117 also significantly reduced fractional exhaled nitric oxide before AIC at day 83; and significantly reduced the allergen-induced increase in % sputum eosinophil count. Pulmonary delivery of biologics directly to the airway mucosal surface has several advantages over parenteral routes, particularly in treating airway diseases such as asthma. Inhaler delivered biologics, such as CSJ117 are innovative and attractive methods of future precision treatment of asthma, and other respiratory diseases.

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.

The role of type 2 innate lymphoid cells in eosinophilic asthma

2019 ◽  
Vol 106 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Brittany M. Salter ◽  
Michael Aw ◽  
Roma Sehmi
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Eosinophilic Asthma

scholarly journals AscarisLarval Infection and Lung Invasion Directly Induce Severe Allergic Airway Disease in Mice

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Jill E. Weatherhead ◽  
Paul Porter ◽  
Amy Coffey ◽  
Dana Haydel ◽  
Leroy Versteeg ◽  
...  
Keyword(s):  
Airway Remodeling ◽  
Periodic Acid ◽  
Airway Disease ◽  
Allergic Airway Disease ◽  
Interleukin 4 ◽  
Lung Pathology ◽  
Periodic Acid Schiff ◽  
Content Type ◽  
Larval Migration

ABSTRACTAscaris lumbricoides(roundworm) is the most common helminth infection globally and a cause of lifelong morbidity that may include allergic airway disease, an asthma phenotype. We hypothesize thatAscarislarval migration through the lungs leads to persistent airway hyperresponsiveness (AHR) and type 2 inflammatory lung pathology despite resolution of infection that resembles allergic airway disease. Mice were infected withAscarisby oral gavage. Lung AHR was measured by plethysmography and histopathology with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) stains, and cytokine concentrations were measured by using Luminex Magpix.Ascaris-infected mice were compared to controls or mice with allergic airway disease induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA).Ascaris-infected mice developed profound AHR starting at day 8 postinfection (p.i.), peaking at day 12 p.i. and persisting through day 21 p.i., despite resolution of infection, which was significantly increased compared to controls and OVA/OVA mice.Ascaris-infected mice had a robust type 2 cytokine response in both the bronchoalveolar lavage (BAL) fluid and lung tissue, similar to that of the OVA/OVA mice, including interleukin-4 (IL-4) (P < 0.01 andP< 0.01, respectively), IL-5 (P < 0.001 andP < 0.001), and IL-13 (P < 0.001 andP < 0.01), compared to controls. By histopathology,Ascaris-infected mice demonstrated early airway remodeling similar to, but more profound than, that in OVA/OVA mice. We found thatAscarislarval migration causes significant pulmonary damage, including AHR and type 2 inflammatory lung pathology that resembles an extreme form of allergic airway disease. Our findings indicate that ascariasis may be an important cause of allergic airway disease in regions of endemicity.

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 Immunization of BALB/c Mice with Killed Neospora caninum Tachyzoite Antigen Induces a Type 2 Immune Response and Exacerbates Encephalitis and Neurological Disease

2000 ◽  
Vol 7 (6) ◽  
pp. 893-898 ◽  
Author(s):  
Timothy V. Baszler ◽  
Terry F. McElwain ◽  
Bruce A. Mathison
Keyword(s):  
Immune Response ◽  
Neurological Disease ◽  
Neospora Caninum ◽  
Brain Lesions ◽  
Lymphoid Cells ◽  
Interleukin 4 ◽  
Type 2 Immune Response ◽  
Parasite Challenge

ABSTRACT BALB/c mice were immunized subcutaneously with solubleNeospora caninum tachyzoite antigen (NSO) entrapped in nonionic surfactant vesicles (NISVs) or administered with Freund's complete adjuvant (FCA). Following virulent parasite challenge, groups of mice immunized with NSO and either NISVs or FCA had clinical neurological disease and increased numbers of brain lesions compared to groups of mice inoculated with FCA, NISVs, or phosphate-buffered saline (PBS) alone. Increased numbers of brain lesions were statistically significant only between mice immunized with NISV-NSO and NISV- or PBS-treated mice. Following parasite challenge, brain inflammatory infiltrates in all experimental and control groups of mice were relatively similar and consisted of compact infiltrates of macrophages admixed with various numbers of lymphoid cells. Increased brain lesions in NSO-immunized mice were associated with increased antigen-specific interleukin 4 (IL-4) secretion and increased IL-4:gamma interferon secretion ratios from splenocytes in vitro and increased antigen-specific immunoglobulin G1 (IgG1):IgG2a ratios in vivo. Thus, immunization with whole killed N. caninum antigen and either liposoidal or Freund's adjuvant induced a type 2 immune response that was associated with worsened disease. The present studies emphasize the need to identify specific N. caninum antigens or other delivery systems that will elicit protective immune responses to neosporosis.

scholarly journals CD8+ Tc2 cells: underappreciated contributors to severe asthma

2019 ◽  
Vol 28 (154) ◽  
pp. 190092 ◽  
Author(s):  
Timothy S.C. Hinks ◽  
Ryan D. Hoyle ◽  
Erwin W. Gelfand
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Stable State ◽  
Lavage Fluid ◽  
Leukotriene B4 ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Prostaglandin D2 ◽  
Eosinophilic Asthma

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8+ T-cells. Extensive murine data reveal the plasticity of CD8+ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.

scholarly journals Benralizumab: From the Basic Mechanism of Action to the Potential Use in the Biological Therapy of Severe Eosinophilic Asthma

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Corrado Pelaia ◽  
Cecilia Calabrese ◽  
Alessandro Vatrella ◽  
Maria Teresa Busceti ◽  
Eugenio Garofalo ◽  
...  
Keyword(s):  
Biological Therapy ◽  
Airway Disease ◽  
Basic Mechanism ◽  
Lymphoid Cells ◽  
Biologic Drugs ◽  
Eosinophilic Asthma ◽  
Interleukin 5 ◽  
Severe Eosinophilic Asthma ◽  
Bronchial Inflammation ◽  
Group 2

Asthma is a very frequent chronic airway disease that includes many different clinical phenotypes and inflammatory patterns. In particular, eosinophilic bronchial inflammation is often associated with allergic as well as nonallergic asthma. The most important cytokine involved in the induction, maintenance, and amplification of airway eosinophilia in asthma is interleukin-5 (IL-5), released by both T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). Hence, IL-5 and its receptor are suitable targets for selective biologic drugs which can play a key role in add-on treatment of severe eosinophilic asthma refractory to corticosteroids. Within such a context, the anti-IL-5 monoclonal antibodies mepolizumab and reslizumab have been developed and approved for biological therapy of uncontrolled eosinophilic asthma. In this regard, on the basis of several successful randomized controlled trials, the anti-IL-5 receptor benralizumab has also recently obtained the approval from US Food and Drug Administration (FDA).

scholarly journals Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Lanlan Mi ◽  
Shaoxuan Zhu ◽  
Jiayu Cai ◽  
Suqing Xu ◽  
Zhengyang Xue ◽  
...  
Keyword(s):  
Bronchopulmonary Dysplasia ◽  
Structural Disorder ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Interleukin 4 ◽  
Control Group ◽  
M2 Macrophages ◽  
Destructive Effect

Bronchopulmonary dysplasia (BPD) is a severe complication of the respiratory system associated with preterm birth. Type 2 innate lymphoid cells (ILC2s) play a major role in tissue homeostasis, inflammation, and wound healing. However, the role in BPD remains unclear. The present study showed that ILC2s, interleukin-4 (IL-4), IL-13, and anti-inflammatory (M2) macrophages increased significantly in BPD mice as compared to the control mice. Administration with recombinant mouse IL-33 amplified the above phenomena and aggravated the alveolar structural disorder and functional injury in mice subjected to BPD, and the opposite was true with anti-ST2 antibody. In addition, the depletion of ILC2s in BPD mice with anti-CD90.2 antibody substantially abolished the destructive effect on BPD. In the treatment of BPD with dexamethasone, the number of ILC2s and M2 macrophages and levels of IL-4 and IL-13 decreased with remission as compared to the control group. This study identified a major destructive role of the ILC2s in BPD that could be attenuated as a therapeutic strategy.

scholarly journals Severe Neutrophilic Asthma: Pathogenesis and Treatment

2022 ◽  
Vol 3 (1) ◽  
pp. 01-13
Author(s):  
Nightingale Syabbalo
Keyword(s):  
Cell Injury ◽  
Inhaled Corticosteroids ◽  
Fungal Infections ◽  
Unmet Need ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
High Dose ◽  
Interleukin 17 ◽  
Airway Epithelial ◽  
Eosinophilic Asthma

Asthma is a common chronic airway disease affecting about 358 million people worldwide, and an estimated 7 million children globally. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids and other modifiers. Among these, are patients with severe neutrophilic asthma. Neutrophilic asthma is a severe phenotype of asthma, characterized by frequent exacerbations, persistent airway obstruction, and poor lung function. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the airways and lungs. Interleukin-17 produced by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines and chemokines for the recruitment, and activation of neutrophils. Interleukin-8 is a powerful chemoattractant and activator of neutrophils. Activated neutrophils produce an oxidative burst, releasing multiple reactive oxygen species, proteinases, cytokines, which cause airway epithelial cell injury, inflammation, airway hyperresponsiveness, and remodeling. Furthermore, exasperated neutrophils due to viral, bacterial or fungal infections, and chemical irritants can release extracellular nucleic acids (DNA), designated as NETs (neutrophil extracellular traps), which are more toxic to the airway epithelial cells, and orchestrate airway inflammation, and release alarmin cytokines. Dysregulated NETs formation is associated with severe asthma. Most patients with neutrophilic asthma are unresponsive to the standard of care, including high dose inhaled corticosteroids, and to targeted biologics, such as mepolizumab, and dupilumab, which are very effective in treating eosinophilic asthma. There is unmet need to explore for novel biologics for the treatment of neutrophilic asthma, and in refining therapies, such as bronchial thermoplasty.

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