scholarly journals Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience

2016 ◽  
Vol 11 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Gilda Varricchi ◽  
Diego Bagnasco ◽  
Matteo Ferrando ◽  
Francesca Puggioni ◽  
Giovanni Passalacqua ◽  
...  
Keyword(s):  
Practical Experience ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Current Evidence ◽  
Blood Leukocytes ◽  
Eosinophilic Asthma ◽  
Gm Csf ◽  
Severe Eosinophilic Asthma ◽  
Nk T Cells ◽  
Group 2

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the β common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5Rα and a common subunit βc shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5Rα compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5.

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 Precision medicine applications for severe asthma

2019 ◽  
Vol 6 (4) ◽  
pp. 117-135
Author(s):  
Orit Gourgy Hacohen ◽  
Shai Cohen
Keyword(s):  
Precision Medicine ◽  
Severe Asthma ◽  
Oral Corticosteroid ◽  
Treatment Options ◽  
Current Evidence ◽  
Blood Eosinophil ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Beneficial Effects ◽  
New Treatment

Asthma is a heterogeneous condition in which multiple pathological pathways manifest with similar symptoms. Severe asthma (SA) is challenging to manage and comprises a significant health and economic burden. Many studies have been conducted in an attempt to define different clinical phenotypes that translate into biological endotypes, with the goal of tailoring treatment based on precision medicine. This review summarizes the current evidence for the treatments of SA, and in particular, the biologic treatments that are currently available: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. We found only limited high-quality direct evidence regarding treatment with anti-IgE (omalizumab) in SA patients. Data regarding anti-interleukin (IL)-5 (mepolizumab, reslizumab and benralizumab) showed beneficial effects in severe eosinophilic asthma (SEA) with different levels of blood eosinophils used in clinical trials. Dupilumab, anti-IL-4/IL-13, was shown to be effective in SEA and is the only agent currently FDA-approved for the indication of oral corticosteroid dependent asthma, regardless of the blood eosinophil level. This review also summarizes the existing knowledge regarding the characteristics of the patient who may respond to the different therapies. As of today, more studies are needed to better understand the diverse mechanisms that underlie SA phenotypes. We have not yet adequately reached the goal of precision medicine. Additional studies are necessary in order to find novel surrogate markers that can predict the response to a specific biologic therapy, especially in patients who are oral corticosteroid dependent. In addition, efforts must be invested into research looking for new treatment options for patients with non-type-2 inflammation SA. Statement of novelty: we review the current evidence regarding tailored treatment therapies in SA, with a particular focus on the knowledge regarding patient selection for specific biologic treatments.

scholarly journals The essential function of IL-33 in metabolic regulation

2020 ◽  
Vol 52 (7) ◽  
pp. 768-775 ◽  
Author(s):  
Wenping Li ◽  
Yiyuan Li ◽  
Jin Jin
Keyword(s):  
Metabolic Regulation ◽  
Underlying Mechanism ◽  
Lymphoid Cells ◽  
Regulatory Function ◽  
Current Evidence ◽  
Metabolic Processes ◽  
Interleukin 33 ◽  
Health And Disease ◽  
Essential Function ◽  
Group 2

Abstract Interleukin-33 (IL-33) is produced by various types of cells under physical or pathological conditions. As a multifunctional partner in health and disease, current evidence reveals that IL-33 also participates in several metabolic processes. IL-33 has been proven to contribute to regulating the activity of ST2+ group 2 innate lymphoid cells and regulatory T cells in adipose, which leads to the shift of insulin sensitivity and glucose clearance in glucose metabolism, thermogenesis, and adipocyte beiging in adipose metabolism. In this review, we briefly summarize the biological characteristics of Il-33 and discuss its regulatory function in glucose and adipose metabolism. By clarifying the underlying mechanism of IL-33, we highlight the crosstalk between immune response and metabolic processes mediated by IL-33.

Eosinophil outer membrane integrins and IL-5, IL-3, GM-CSF receptors expression in severe eosinophilic asthma

2018 ◽  
Author(s):  
Virginija Kalinauskaite-Zukauske ◽  
Ieva Janulaityte ◽  
Andrius Januskevicius ◽  
Rokas Stonkus ◽  
Kestutis Malakauskas
Keyword(s):  
Outer Membrane ◽  
Eosinophilic Asthma ◽  
Gm Csf ◽  
Severe Eosinophilic Asthma

The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma

2020 ◽  
Vol 202 (8) ◽  
pp. 1105-1114 ◽  
Author(s):  
Kentaro Machida ◽  
Michael Aw ◽  
Brittany M. A. Salter ◽  
Xiaotian Ju ◽  
Manali Mukherjee ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Eosinophilic Asthma ◽  
Group 2

scholarly journals IL-33 genetics and epigenetics in immune-related diseases

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Eleonora Di Salvo ◽  
Marco Casciaro ◽  
Sebastiano Gangemi
Keyword(s):  
Secretory Pathway ◽  
Interleukin 1 ◽  
Lymphoid Cells ◽  
Th2 Cells ◽  
Interleukin 33 ◽  
Immune Genes ◽  
Helminthic Infections ◽  
Type 2 Immune Response ◽  
Group 2 ◽  
Diverse Data

AbstractInterleukin-33 (IL-33) is a 30KDa protein, which belongs to the Interleukin-1 cytokine family. It is a crucial regulator of innate and adaptive immune responses. This interleukin is additionally involved in the inflammatory reaction versus helminthic infections. Interleukin 33 acts on group 2 innate lymphoid cells and mast cells macrophages, dendritic cells and CD4 + Th2 cells eliciting a type 2 immune response. Moreover, the cytokine can activate the ST2 of Tregs, demonstrating its ability to downregulate inflammation. IL-33 has also an intracellular function by regulating transcription. The active IL-33 doesn’t have a signal peptide, so it’s not released across a normal secretory pathway; the interleukin is released when the cells are damages and acts like an “alarmin”. Its influence on immune activation could be slightly adjusted via fine epigenetic interactions involving cascade pathways and immune genes. Due to the diverse data emerged from different experimental research, we decided span literature to clarify, as much as possible, how IL-33 is influenced by and influence gene expression. The authors reported how its balance is influenced, according to the tissue considered. Fundamental for immune-related diseases, IL-33 has a key role in controlling inflammation. The understanding of the cytokine switch will be fundamental in a near future in order to block or activate some immune pathways. In fact, we could control interleukins effects not only by monoclonal antibodies but also by using siRNA or miRNAs for silencing or expressing key genes.

scholarly journals Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience

2018 ◽  
Vol 12 ◽  
pp. 175346661880849 ◽  
Author(s):  
Rosalia Emma ◽  
Jaymin B. Morjaria ◽  
Virginia Fuochi ◽  
Riccardo Polosa ◽  
Massimo Caruso
Keyword(s):  
Severe Asthma ◽  
Conventional Therapy ◽  
Atopic Asthma ◽  
Current Evidence ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Number Of Patients ◽  
Chronic Inflammatory Condition ◽  
Long Term Treatment ◽  
Asthma Patients

Asthma is a chronic inflammatory condition involving the airways with varying pathophysiological mechanisms, clinical symptoms and outcomes, generally controlled by conventional therapies including inhaled corticosteroids and long-acting β2 agonists. However, these therapies are unable to successfully control symptoms in about 5–10% of severe asthma patients. Atopic asthma, characterized by high immunoglobulin (Ig)E or eosinophilia, represents about 50% of asthmatic patients. Interleukin (IL)-5 is the main cytokine responsible of activation of eosinophils, hence therapeutic strategies have been investigated and developed for clinical use. Biologics targeting IL-5 and its receptor (first mepolizumab and subsequently, reslizumab and benralizumab), have been recently approved and used as add-on therapy for severe eosinophilic asthma resulting in a reduction in the circulating eosinophil count, improvement in lung function and exacerbation reduction in asthma patients. Despite these biologics having been approved for stratified severe asthma patients that remain uncontrolled with high doses of conventional therapy, a number of patients may be eligible for more than one biologic. Presently, the lack of head-to-head studies comparing the biological agents among themselves and with conventional therapy make the choice of optimal therapy for each patient a challenge for clinicians. Moreover, discontinuation of these treatments, implications for efficacy or adverse events, in particular in long-term treatment, and needs for useful biomarkers are still matters of debate. In this review we evaluate to date, the evidence on mepolizumab that seems to demonstrate it is a well-tolerated and efficacious regimen for use in severe eosinophilic asthma, though more studies are still required.

scholarly journals Interleukin-33 and thymic stromal lymphopoietin, but not interleukin-25, are crucial for development of airway eosinophilia induced by chitin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ken Arae ◽  
Masashi Ikutani ◽  
Kotaro Horiguchi ◽  
Sachiko Yamaguchi ◽  
Youji Okada ◽  
...  
Keyword(s):  
Allergic Diseases ◽  
Lymphoid Cells ◽  
House Dust Mites ◽  
Atopic Asthma ◽  
Th2 Cells ◽  
Airway Eosinophilia ◽  
Interleukin 33 ◽  
Group 2 ◽  
Underlying Mechanisms ◽  
Mechanisms Of Development

AbstractExposure to various antigens derived from house dust mites (HDM) is considered to be a risk factor for development of certain allergic diseases such as atopic asthma, atopic dermatitis, rhinitis and conjunctivitis. Chitin is an insoluble polysaccharide (β-(1–4)-poly-N-acetyl-d-glucosamine) and a major component in the outer shell of HDMs. Mice exposed to chitin develop asthma-like airway eosinophilia. On the other hand, several lines of evidence show that the effects of chitin on immune responses are highly dependent on the size of chitin particles. In the present study, we show that chitin induced production of IL-33 and TSLP by alveolar and bronchial epithelial cells, respectively, in mice. IL-25, IL-33 and TSLP were reported to be important for group 2 innate lymphoid cell (ILC2)-, but not Th2 cell-, dependent airway eosinophilia in a certain model using chitin beads. Here, we show that—in our murine models—epithelial cell-derived IL-33 and TSLP, but not IL-25, were crucial for activation of resident lung Th2 cells as well as group 2 innate lymphoid cells (ILC2s) to produce IL-5, resulting in development of chitin-induced airway eosinophilia. Our findings provide further insight into the underlying mechanisms of development of HDM-mediated allergic disorders.

scholarly journals Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Julia Gschwend ◽  
Samantha P.M. Sherman ◽  
Frederike Ridder ◽  
Xiaogang Feng ◽  
Hong-Erh Liang ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Environmental Cues ◽  
Alveolar Epithelial ◽  
Gm Csf ◽  
Proliferation And Differentiation ◽  
Before And After ◽  
Group 2

Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.

scholarly journals Type-2 CD8+ T lymphocytes responsive to PGD2 and LTE4 in severe eosinophilic asthma

2018 ◽  
Author(s):  
Bart Hilvering ◽  
Timothy SC Hinks ◽  
Linda Stöger ◽  
Emanuele Marchi ◽  
Maryam Salimi ◽  
...  
Keyword(s):  
Th2 Cells ◽  
Eosinophilic Asthma ◽  
Independent Manner ◽  
Severe Eosinophilic Asthma ◽  
Cysteinyl Leukotriene ◽  
Cytokines And Chemokines ◽  
Models Of Disease

ABSTRACTThe functions and in vivo roles of type-2 CD8+ T cells in humans have not been well defined and this cell type has been largely overlooked in models of disease. We investigated this in the context of severe asthma with persistent airway eosinophilia - a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

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