Effect of Inhaled Interleukin-4 on Airway  Hyperreactivity in Asthmatics

Shi, Huan‐Zhong; Deng, Jingmin; Xu, Hui; Nong, Zhi-Xin; Xiao, Changqing; Liu, Zhiming; Qin, Simeng; Jiang, Hai‐Xing; Liu, Guangnan; Chen, Yiqiang

doi:10.1164/ajrccm.157.6.9710023

Cited by 84 publications

(50 citation statements)

References 22 publications

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“…Therefore, a possible explanation for the remarkable effects of DM-IL-4 in our experiments can be found in the neutralization of the up-regulation of the IL-5 secretion from the human Th2 lymphocytes by . This fits with the clinical observation of increased airway responsiveness after IL-4 inhalation, which was associated with an IL-5-driven eosinophil influx (40). DM-IL-4 also blocks all activities of IL-13 including its possible direct effects on smooth muscle cells on which the IL-13 receptor was demonstrated (41).…”

Section: Discussionsupporting

confidence: 83%

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

Tournoy

Kips

Pauwels

2001

The Journal of Immunology

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The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-γ after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

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Section: Discussionsupporting

confidence: 83%

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

Tournoy

Kips

Pauwels

2001

The Journal of Immunology

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“…Furthermore, research in mouse models has established the critical roles that Th2 cytokines play in the pathophysiology of asthma, including mucus hypersecretion and AHR [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], and a recent study emphasised the importance of IL-4 and IL-13 in airway dysfunction and remodelling in response to chronic allergen exposure [50]. In human studies, administration of recombinant IL-4 resulted in AHR in asthmatic subjects [51], whereas IL-12 suppressed eosinophils in blood and sputum (without affecting AHR [52]). Furthermore, clinically useful drugs, including inhaled corticosteroids, potently suppress Th2 cytokine gene expression [53,54].…”

Section: Th2 Cells Asthma and Atopymentioning

confidence: 99%

T-helper cell type-2 regulation in allergic disease

Georas

Guo

Fanis

et al. 2005

European Respiratory Journal

154

101

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Substantial experimental evidence now supports the notion that allergic diseases are characterised by a skewing of the immune system towards a T-helper cell type-2 (Th2) phenotype.Studies using both human and mouse model systems have provided key evidence for the role that Th2 cytokines play in driving many of the hallmarks of allergic inflammation. Furthermore, the signalling pathways by which Th2 cytokines exert their effects on airway target cells are rapidly being elucidated, and antagonists of the Th2 pathway are under active development.In this review, the current knowledge of the role of T-helper cell type-2 cells in asthma is summarised, focusing on how and where T-helper cell type-2 cells differentiate from naïve precursors. The signalling molecules and transcription factors involved in T-helper cell type-2 differentiation will be reviewed in detail, in an attempt to translate studies using genetically modified mice into meaningful insights about asthma and other allergic diseases.

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“…IL4 has been shown to play a crucial role in the pathogenesis of allergic disease including bronchial asthma, and IL4 increases airway responsiveness by recruiting eosinophils into the airway in patients with allergic bronchial asthma. In addition, IL10 inhibits eosinophil survival and IL4 induces IgE synthesis (Jeannin et al 1998;Shi et al 1998). These functions of the two genes are deeply associated with their polymorphisms.…”

Section: Introductionmentioning

confidence: 99%

Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy

et al. 2004

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Cytokines, having central functions in immunological and inflammatory process, are always expected to play important roles in the pathogenesis of various diseases, such as asthma. Genetic polymorphisms of those cytokine and cytokine receptor genes are the focus of genetic association studies. In an effort to identify gene(s) whose variant(s) are involved in the development of asthma, we examined the genetic effects of 19 single nucleotide polymorphisms in eight cytokine and cytokine receptor genes, including IL1A, IL1B, IL2, IL3, IL4, IL8, IL10, and IL5RA, on asthma and atopy. Nineteen single nucleotide polymorphisms in eight cytokine and cytokine receptor genes were genotyped using the single-base extension method in a Korean asthma cohort (n=723). Logistic regression and multiple regressions were used for statistical analyses controlling for smoking, age, and gender as covariables. Genetic association analysis of polymorphisms revealed that one exonic (exon 1), IL3+79T>C (Ser27Pro), showed significant association with the risk of asthma and atopy. The Pro allele had shown dominant and protective effects on development of asthma in nonatopic subjects (P=0.002) and also showed significant association with the risk of atopy in normal control subjects (P=0.007). This information about the genetic association of important genes with asthma might provide valuable insights into strategies for the pathogenesis of asthma and atopy.

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Effect of Inhaled Interleukin-4 on Airway Hyperreactivity in Asthmatics

Cited by 84 publications

References 22 publications

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent

T-helper cell type-2 regulation in allergic disease

Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy

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