scholarly journals Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eva Conde ◽  
Romain Bertrand ◽  
Bianca Balbino ◽  
Jonathan Bonnefoy ◽  
Julien Stackowicz ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Mouse Models ◽  
Cost Effective ◽  
Interleukin 4 ◽  
Mucus Production ◽  
Post Vaccination ◽  
Type 2 Cytokines ◽  
Therapeutic Monoclonal Antibodies

AbstractAllergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.

scholarly journals Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype

2021 ◽  
Vol 8 ◽  
Author(s):  
Miguel Gonzalez Acera ◽  
Jay V. Patankar ◽  
Leonard Diemand ◽  
Britta Siegmund ◽  
Markus F. Neurath ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Mouse Models ◽  
Intestinal Inflammation ◽  
Mucosal Healing ◽  
Th2 Cells ◽  
Parasitic Infections ◽  
Inflammatory Conditions ◽  
Elevated Type ◽  
Type 2 Cytokines

Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.

Ligation of CD2 Provides a Strong Helper Signal for the Production of the Type 2 Cytokines Interleukin-4 and -5 by Memory T Cells

1997 ◽  
Vol 181 (1) ◽  
pp. 76-85 ◽  
Author(s):  
Xiaohui Peng ◽  
Ahmad Kasran ◽  
Dominique Bullens ◽  
Jan L. Ceuppens
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Interleukin 4 ◽  
Type 2 Cytokines

scholarly journals Diverse innate stimuli activate basophils through pathways involving Syk and IκB kinases

2021 ◽  
Vol 118 (12) ◽  
pp. e2019524118
Author(s):  
Christophe Pellefigues ◽  
Palak Mehta ◽  
Sally Chappell ◽  
Bibek Yumnam ◽  
Sam Old ◽  
...  
Keyword(s):  
Growth Factors ◽  
Signaling Pathways ◽  
Allergic Diseases ◽  
Basophil Activation ◽  
Interleukin 4 ◽  
Type I ◽  
Direct Effects ◽  
Gm Csf ◽  
Type 2 Cytokines

Mature basophils play critical inflammatory roles during helminthic, autoimmune, and allergic diseases through their secretion of histamine and the type 2 cytokines interleukin 4 (IL-4) and IL-13. Basophils are activated typically by allergen-mediated IgE cross-linking but also by endogenous “innate” factors. The aim of this study was to identify the innate stimuli (cytokines, chemokines, growth factors, hormones, neuropeptides, metabolites, and bacterial products) and signaling pathways inducing primary basophil activation. Basophils from naïve mice or helminth-infected mice were cultured with up to 96 distinct stimuli and their influence on basophil survival, activation, degranulation, and IL-4 or IL-13 expression were investigated. Activated basophils show a heterogeneous phenotype and segregate into distinct subsets expressing IL-4, IL-13, activation, or degranulation markers. We find that several innate stimuli including epithelial derived inflammatory cytokines (IL-33, IL-18, TSLP, and GM-CSF), growth factors (IL-3, IL-7, TGFβ, and VEGF), eicosanoids, metabolites, TLR ligands, and type I IFN exert significant direct effects on basophils. Basophil activation mediated by distinct upstream signaling pathways is always sensitive to Syk and IκB kinases-specific inhibitors but not necessarily to NFAT, STAT5, adenylate cyclase, or c-fos/AP-1 inhibitors. Thus, basophils are activated by very diverse mediators, but their activation seem controlled by a core checkpoint involving Syk and IκB kinases.

Bariatric Surgery as a Long-Term Treatment for Type 2 Diabetes/Metabolic Syndrome

2020 ◽  
Vol 71 (1) ◽  
pp. 1-15
Author(s):  
Zubaidah Nor Hanipah ◽  
Philip R. Schauer
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Surgery ◽  
Lifestyle Modification ◽  
Cost Effective ◽  
Term Treatment ◽  
Sustained Weight Loss ◽  
Long Term Treatment ◽  
Perioperative Risks

Metabolic surgery is increasingly becoming recognized as a more effective treatment for patients with type 2 diabetes (T2D) and obesity as compared to lifestyle modification and medical management alone. Both observational studies and clinical trials have shown metabolic surgery to result in sustained weight loss (20–30%), T2D remission rates ranging from 23% to 60%, and improvement in cardiovascular risk factors such as hypertension and dyslipidemia. Metabolic surgery is cost-effective and relatively safe, with perioperative risks and mortality comparable to low-risk procedures such as cholecystectomy, hysterectomy, and appendectomy. International diabetes and medical organizations have endorsed metabolic surgery as a standard treatment for T2D with obesity.

Possible Involvement of Type 2 Cytokines in Alloknesis in Mouse Models of Menopause and Dry Skin

2021 ◽  
Author(s):  
Nao Ichimasu ◽  
Yue Chen ◽  
Keisuke Kobayashi ◽  
So Suzuki ◽  
Sakiko Chikazawa ◽  
...  
Keyword(s):  
Mouse Models ◽  
Dry Skin ◽  
Type 2 Cytokines

scholarly journals Defining type 2 asthma and patients eligible for dupilumab in Italy: a biomarker-based analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Giorgio Walter Canonica ◽  
Francesco Blasi ◽  
Nunzio Crimi ◽  
Pierluigi Paggiaro ◽  
Alberto Papi ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Immunoglobulin E ◽  
Cost Effective ◽  
Mucus Production ◽  
Clinical Indicators ◽  
Asthmatic Patients ◽  
Eligible Population ◽  
Asthma Patients ◽  
Severe Type

Abstract Background Asthma is a chronic disease characterized by airway hyperresponsiveness, inflammation and mucus production. In Type 2 asthma, two phenotypic components are often co-expressed (eosinophilic and allergic). Elevated biomarker levels, such as eosinophils (EOS), fraction of exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), are key clinical indicators of Type 2 inflammation. Dupilumab has been recently approved for the treatment of uncontrolled severe Type 2 asthma. Type 2 asthma includes allergic and/or eosinophilic phenotypes. The aim of this analysis was to estimate the dupilumab-eligible population in Italy and characterize it by expected biomarker status. Methods A 4-step approach was carried out to calculate dupilumab-eligible population. The approach consisted in: (1) estimating the total number of asthma patients in Italy (using 2016–2017 Italian-adapted Global Initiative for Asthma -GINA- guidelines); (2) estimating the number of severe asthma patients with poorly controlled or uncontrolled disease (using the findings of two recent administrative claim analyses conducted in Italy); (3) stratifying the severe uncontrolled population by biomarker levels (EOS, FeNO and IgE) according to the outcomes of the QUEST trial (a clinical study assessing the efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma; NCT02414854); (4) identifying the sub-populations of severe uncontrolled asthma patients characterised by raised blood EOS and/or FeNO level (thus indicated to receive dupilumab). Results According to these estimates, about 3.3 million asthmatic patients live in Italy (6.10% of the population). Of them, almost 20 thousand (N = 19,960) have uncontrolled severe asthma. Dupilumab-eligible patients would be N = 15,988, corresponding to 80.1% of the total uncontrolled severe population. Most of these patients (89.3%; N = 14,271) have at least an increase of EOS level, while slightly more than half (51.9%; N = 8,303) have raised levels of both biomarkers. Increased FeNO levels without increased EOS are observed less frequently (N = 1,717; 10.7% of the eligible population). Conclusions There is a strong rationale for testing all asthma biomarkers during diagnosis and disease follow-up. Given the large availability and the limited costs, these tests are cost-effective tools to detect severe Type 2 asthma, stratify patients by phenotype, and drive appropriate treatment decisions.

scholarly journals A Balanced Type 1/Type 2 Response Is Associated with Long-Term Nonprogressive Human Immunodeficiency Virus Type 1 Infection

2002 ◽  
Vol 76 (18) ◽  
pp. 9011-9023 ◽  
Author(s):  
Nesrina Imami ◽  
Antonio Pires ◽  
Gareth Hardy ◽  
Jamie Wilson ◽  
Brian Gazzard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Interleukin 4 ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Previous reports have emphasized the requirements for strong type 1 cell-mediated responses in the control of human immunodeficiency virus type 1 (HIV-1). HIV-1 Gag p24-specific CD4 helper T-lymphocyte (HTL) responses have been shown to inversely correlate with viral burden in HIV-1-infected individuals. In this study, peripheral blood mononuclear cells from 70 individuals with chronic progressive HIV-1 infection (clinical progressors), 10 clinical nonprogressors, and 3 immunologically discordant progressors were assessed for HTL proliferation and type 1/type 2 cytokine production. Clinical progressors lacked functional HIV-1-specific HTLs with proliferative and cytokine-producing capacity. Clinical nonprogressors were found to respond to a wide range of HIV-1 antigens from different clades, producing both type 1 and type 2 cytokines. Immunologically discordant progressors responded strongly to clade B Gag p24 with a type 1 cytokine profile but not to other antigens. Thus, in contrast to clinical nonprogressors, neither progressors nor immunologically discordant progressors secreted interleukin-4 (IL-4) in response to HIV-1 antigens. Both clinical nonprogressors and immunologically discordant progressors responded broadly to B clade Gag p24-overlapping peptides. However, IL-4 production in the nonprogressors was restricted to a limited number of p24 peptides. No HIV-1-specific T-cell responses were seen in 20 seronegative controls. Additionally, we observed a rapid type 1 to type 2 shift in the response of one immunologically discordant progressor upon onset of clinical symptoms. These results suggest that a balanced type 1/type 2 profile correlates with successful long-term control of HIV-1.

scholarly journals Defining Type 2 asthma and patients eligible for dupilumab in Italy: a biomarker-based analysis

2020 ◽  
Author(s):  
Giorgio Walter Canonica ◽  
Francesco Blasi ◽  
Nunzio Crimi ◽  
Pierluigi Paggiaro ◽  
Alberto Papi ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Immunoglobulin E ◽  
Cost Effective ◽  
Mucus Production ◽  
Clinical Indicators ◽  
Asthmatic Patients ◽  
Eligible Population ◽  
Asthma Patients ◽  
Severe Type

Abstract Background Asthma is a chronic disease characterized by airway hyperresponsiveness, inflammation and mucus production. In Type 2 asthma, two phenotypic components are often co-expressed (eosinophilic and allergic). Elevated biomarker levels, such as eosinophils (EOS), fraction of exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), are key clinical indicators of Type 2 inflammation. Dupilumab has been recently approved for the treatment of uncontrolled severe Type 2 asthma. Type 2 asthma includes allergic and/or eosinophilic phenotypes. The aim of this analysis was to estimate the dupilumab-eligible population in Italy and characterize it by expected biomarker status.Methods A 4-step approach was carried out to calculate dupilumab-eligible population. The approach consisted in: 1) estimating the total number of asthma patients in Italy (using 2016–2017 Italian-adapted Global Initiative for Asthma -GINA- guidelines); 2) estimating the number of severe asthma patients with poorly controlled or uncontrolled disease (using the findings of two recent administrative claim analyses conducted in Italy); 3) stratifying the severe uncontrolled population by biomarker levels (EOS, FeNO and IgE) according to the outcomes of the QUEST trial (a clinical study assessing the efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma; NCT02414854); 4) identifying the sub-populations of severe uncontrolled asthma patients characterised by raised blood EOS and/or FeNO level (thus indicated to receive dupilumab).Results According to these estimates, about 3.3 million asthmatic patients live in Italy (6.10% of the population). Of them, almost 20 thousand (N = 19,960) have uncontrolled severe asthma. Dupilumab-eligible patients would be N = 15,988, corresponding to 80.1% of the total uncontrolled severe population. Most of these patients (89.3%; N = 14,271) have at least an increase of EOS level, while slightly more than half (51.9%; N = 8,303) have raised levels of both biomarkers. Increased FeNO levels without increased EOS are observed less frequently (N = 1,717; 10.7% of the eligible population).Conclusions There is a strong rationale for testing all asthma biomarkers during diagnosis and disease follow-up. Given the large availability and the limited costs, these tests are cost-effective tools to detect severe Type 2 asthma, stratify patients by phenotype, and drive appropriate treatment decisions.

scholarly journals Jia-Wei-Yu-Ping-Feng-San Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation in Allergic Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingna Xue ◽  
Cui Li ◽  
Guangbo Ge ◽  
Shaoyan Zhang ◽  
Liming Tian ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Asthma ◽  
Airway Hyperresponsiveness ◽  
Airway Resistance ◽  
Inflammatory Cell ◽  
Inflammatory Cells ◽  
Type 2 Cytokines ◽  
Group 2

The incidence of asthma has increased in recent decades. Although corticosteroids and bronchodilators are used in clinical practice, the control of asthma remains a challenge. Allergic asthma is characterized airway inflammation mediated by type 2 immune response. Group 2 innate lymphoid cells (ILC2s) are an important source of type 2 cytokines IL-5 and IL-13, which contribute to the progress of asthma. Jia-Wei-Yu-Ping-Feng-San (JWYPFS), a traditional Chinese medicine, has been widely used to treat asthma in China. In this study we investigated the mechanisms of JWYPFS in the treatment of asthma, especially the effect on ILC2s important in airway inflammation. Female C57BL/6 mice were sensitized and challenged with OVA to establish a model of allergic asthma. Airway hyperresponsiveness was examined by direct airway resistance analysis. Inflammatory cell counts were determined in bronchoalveolar lavage fluid (BALF). Inflammatory cell infiltration and mucus hypersecretion in lung tissue sections was observed by HE and PAS staining, respectively. The numbers and proportions of ILC2s as well as the ILC2s-related transcription factors GATA3, IRF4, and type 2 cytokines were measured in lung tissue samples. Additionally, ILC2s were collected from mouse lung; ILC2s-related cytokines and GATA3 and IRF4 were evaluated after IL-33-induced activation of ILC2s in vitro. Elevated inflammatory cells, mucus secretion, airway hyperresponsiveness and type 2 cytokines in the OVA-treated asthma group indicated that an allergic asthma model had been established. JWYPFS treatment attenuated airway resistance and reduced inflammatory cells including eosinophils, and inhibited mucus production and type 2 cytokines in these asthmatic mice. Moreover, JWYPFS treatment dramatically decreased the numbers and proportions of ILC2s and the mRNA levels of GATA3 and IRF4. In an in vitro experiment JWYPFS significantly suppressed GATA3, IRF4 and type 2 cytokine expression, including IL-5 and IL-13 in IL-33-stimulated ILC2s. JWYPFS alleviates ILC2s-mediated airway inflammation, suggesting that JWYPFS might be an effective agent to treat allergic asthma.

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