Clinical and immunological effects of low‐dose IFN‐<i>α</i> treatment in patients with corticosteroid‐resistant asthma

Simon, Hans‐Uwe; Seelbach, H.; Ehmann, Rainer; Schmitz, M. Lienhard

doi:10.1046/j.1398-9995.2003.00424.x

Cited by 96 publications

(80 citation statements)

References 32 publications

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“…Interestingly, despite concerns about side effects, IFN-␣ treatment has been shown to be a successful option in the treatment of steroid-resistant asthma, and its mechanisms of actions are thought to involve the promotion of a Th1, rather than a Th2, immune response, thus disrupting the cycle of eosinophilic inflammation and airway hyperreactivity (24,25). Furthermore, it was shown that histamine, released during allergic inflammation, inhibits the secretion of IFN-␣ from plasmacytoid dendritic cells, which could promote a strong Th2 response, as in allergic inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection

Meissner

Swain

Tighe

et al. 2005

The Journal of Immunology

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Despite the advent of highly active antiretroviral therapy, pulmonary complications in AIDS are a common clinical problem. Pneumocystis jiroveci infection causes a life-threatening pneumonia, especially in individuals with CD4 T cell deficiencies as occurs in AIDS. Although Pneumocystis sp. is an extracellular fungal pathogen, CD8 T cells are the predominant lymphocyte recruited to the lung in CD4-deficient humans and mice during Pneumocystis pneumonia, and we have found that these CD8 T cells are responsible for subsequent lung damage in CD4 T cell-depleted mice. Comparing CD4 T cell-depleted IFN-α receptor knockout (KO) mice to wild-type mice, we found that this CD8 T cell recruitment and lung damage is type I IFN (IFN-αβ) dependent. However, in both CD4 competent, wild-type and IFN-α receptor (IFNAR) KO mice, Pneumocystis infection leads to an eosinophilic granulocyte influx with bronchial epithelial changes as seen in asthma. This response is delayed in IFNAR KO mice, as is pathogen clearance. Although the inflammation is transient in wild-type animals and resolves upon Pneumocystis clearance, it is more severe and persists through day 35 postinfection in IFNAR KO mice, leading to fibrosis. In addition, IFNAR KO, but not wild-type, mice mount a Pneumocystis-specific IgE response, an indicator of allergic sensitization. Thus, in the absence of IFNAR signaling and CD4 T cells, Pneumocystis-mediated lung damage does not occur, whereas in CD4-competent animals, the absence of IFNAR signaling results in an exacerbated Th2 response, asthma-like symptoms, and fibrosis. Therefore, both CD4 T cell- and type I IFN-mediated mechanisms can determine pulmonary complications from Pneumocystis infection.

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Section: Discussionmentioning

confidence: 99%

“…By taking advantage of its regulatory influence on the induction of Th1 responses (21)(22)(23), IFN-␣ has recently been used successfully in the treatment of steroid-resistant asthma and related diseases where an exaggerated Th2 immune response leads to eosinophilic lung disease (24,25).…”

mentioning

confidence: 99%

Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection

Meissner

Swain

Tighe

et al. 2005

The Journal of Immunology

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“…The molecular mechanism for these defects in innate immunity is not yet understood. Low-dose IFN-α seems to give marked benefit in patients with severe corticosteroid-resistant asthma but again the mechanism is unknown (30).…”

Section: Figurementioning

confidence: 99%

The cytokine network in asthma and chronic obstructive pulmonary disease

Barnes¹

2008

J. Clin. Invest.

835

714

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Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases. IntroductionThe most common inflammatory diseases of the airways are asthma and chronic obstructive pulmonary disease (COPD), and the incidence of both is increasing throughout the world. The prevalence of asthma in developed countries is approximately 10% in adults and even higher in children, whereas in developing countries, the prevalence is lower but increasing rapidly. The global prevalence of COPD is approximately 10% among individuals over the age of 40 years. Asthma often starts in early childhood and is characterized by intermittent wheezing and shortness of breath. In contrast, the predominant symptom in COPD is shortness of breath on exertion, which is persistent and slowly progressive. Although the clinical symptoms of both diseases are caused by airway narrowing as a result of inflammation in the airways, there are marked differences in the patterns of underlying inflammation.Cytokines play a key role in orchestrating the chronic inflammation of asthma and COPD by recruiting, activating, and promoting the survival of multiple inflammatory cells in the respiratory tract (Figure 1, Figure 2, and Table 1). Over 50 cytokines have now been identified in asthma and COPD, but their role in the pathophysiology of these complex airway diseases is often unclear. For the purpose of this Review, cytokines are classified into lymphokines (cytokines that are secreted by T cells and regulate immune responses), proinflammatory cytokines (cytokines that amplify and perpetuate the inflammatory process), growth factors (cytokines that promote cell survival and result in structural changes in the airways), chemokines (cytokines that are chemotactic for inflammatory cells), and antiinflammatory cytokines (cytokines that negatively modulate the inflammatory response), although many of these functions may overlap. Where possible, I have focused on human studies and have emphasized any therapeutic interventions that have been made.

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“…Regardless, our study identifies a new family of candidate genes for asthma/atopy association studies, for studies of the relationship between viral infections and the development or exacerbation of asthma, 49,50 and for pharmacogenetic studies of the differential response to IFN-a therapy in corticosteroid-resistant asthma and other atopic diseases. [27][28][29][30] …”

Section: Discussionmentioning

confidence: 99%

“…24 Furthermore, reduced levels of IFN-a in patients with the Th2-associated diseases asthma and atopy have been reported, 25,26 and treatment with IFN-a therapy improves clinical symptoms in some patients. [27][28][29][30] Thus, we hypothesized that variation in one or more of these genes could modulate expression levels or function of the type I interferons and, as a result, influence the development or course of asthma and atopic diseases.…”

Section: Introductionmentioning

confidence: 99%

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

et al. 2006

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A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003oPo0.05) with asthma, bronchial hyper-responsiveness (BHR), and atopy were observed with individual variants or genes, spanning the entire 400 kb region. However, pairwise combinations of haplotypes between genes showed highly significant associations with different phenotypes (Po10 À5 ) that were localized to specific pairs of genes or regions of this cluster. These results suggest that variation in multiple genes in the type I IFN cluster on 9p22 contribute to asthma and atopy susceptibility, and that not all genes contribute equally to all phenotypes.

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Clinical and immunological effects of low‐dose IFN‐α treatment in patients with corticosteroid‐resistant asthma

Cited by 96 publications

References 32 publications

Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection

Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection

The cytokine network in asthma and chronic obstructive pulmonary disease

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

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