Treatment of steroid‐dependent asthma with recombinant interferon‐gamma

Boguniewicz, Mark; Schneider, Lynda C.; Milgrom, Henry; Newell, David R.; Kelly, Nicole; Tam, Patrick; Izu, Allen; Jaffe, Howard S.; Bucalo, L. R.; Leung, Donald Y.M.

doi:10.1111/j.1365-2222.1993.tb00367.x

Cited by 53 publications

(23 citation statements)

References 25 publications

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“…The results obtained in our study with regard to efficacy agree in part with those obtained by Boguniewicz et al [34], who conducted a double-blind placebo-controlled study in which subcutaneous IFN-γ was administered over 90 days in 20 steroid-dependent asthmatic patients, without significant clinical improvement at the end of the study. …”

Section: Discussionsupporting

confidence: 81%

“…Several authors [35,36,37] have shown that IFN-γ administration slows eosinophilia in the airways as well as systemic eosinophilia. Boguniewicz et al [34] found a decrease in peripheral eosinophilia in 31% of cases treated with IFN-γ compared to an increase in eosinophilia in 8.5% of the placebo group. Animal models of bronchial atopic asthma where IFN-γ has been administered intranasally, intratracheally, intravenously or in nebulized form have confirmed this IFN-γ-dependent effect.…”

Section: Discussionmentioning

confidence: 99%

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Immunoglobulin E-Dependent Regulation of the CCR3 Chemokine Receptor by Interferon-Gamma in Atopic Asthmatics

García-Vega¹,

Rodríguez-Perez²,

Bermúdez-Badell³

et al. 2008

Int Arch Allergy Immunol

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Background: The chemokine receptor CCR3 mediates the migration of cells that play an important role in the pathogenesis of asthma to inflammatory foci. Interferon (IFN)-γ is known to downregulate the expression of some chemokine receptors. Therefore, we decided to analyze the regulation of CCR3 by IFN-γ in asthmatics and to characterize the dependence of this process on immunoglobulin E (IgE) levels. Methods: Atopic asthmatics were treated with IFN-γ or placebo, and the IgE concentration in the blood was measured using an ultra-micro-ELISA for total IgE. Mononuclear cells from patients and controls were isolated by Ficoll-Hypaque gradient and incubated in the absence or presence of IFN-γ for different periods of time. After incubation, the cells were washed and lysed for RT-PCR analysis, which was performed using a Perkin-Elmer kit. Results: IFN-γ treatment apparently improved the evaluated clinical variables; however, the differences were not significant compared to the placebo group. We found that IFN-γ downregulated CCR3 mRNA expression ex vivo and in vivo in those patients with IgE levels higher than 500 IU/ml, whereas IFN-γ upregulated CCR3 mRNA expression in patients with IgE levels lower than 500 IU/ml. Correspondence between ex vivo and in vivo results was observed using this approach. There was found to be a direct correlation between total serum IgE and CCR3 mRNA expression. Conclusions: In those asthmatic patients with high levels of IgE, who are thus susceptible to downregulation of CCR3 by IFN-γ, a significant therapeutic effect with systemic IFN-γ might be expected.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Immunoglobulin E-Dependent Regulation of the CCR3 Chemokine Receptor by Interferon-Gamma in Atopic Asthmatics

García-Vega¹,

Rodríguez-Perez²,

Bermúdez-Badell³

et al. 2008

Int Arch Allergy Immunol

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“…Moreover, several studies have reported that intranasal administration of IFN-␥ effectively inhibited goblet cell metaplasia and AHR in a mouse model (34,35,42). However, no beneficial effects were observed on AHR or symptom scores with IFN-␥ in patients with asthma (43,44).…”

Section: Discussionmentioning

confidence: 99%

RANTES (CCL5) Regulates Airway Responsiveness after Repeated Allergen Challenge

Koya

Takeda

Kodama

et al. 2006

Am J Respir Cell Mol Biol

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RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term-challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeatedchallenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term-challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-␥ levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-␥-producing CD4 T cells in lung, and IFN-␥ production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti-IFN-␥, administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-␥ and IL-12. Keywords: airway hyperresponsiveness; IFN-␥; IL-12; RANTES (CCL5)Bronchial asthma is a chronic inflammatory airway disease with the features of reversible airway obstruction and nonspecific airway hyperresponsiveness (AHR). Elevated serum IgE levels and inflammatory cell infiltration, especially of eosinophils, mast cells, and CD4ϩ T cells, seems to be involved in the pathogenesis of the disease (1-3). In animal models of acute allergic inflammation, Th2-cell-derived cytokines, notably IL-4, IL-5, IL-9, and IL-13 and C-C chemokine family members such as RANTES (regulated upon activation, normal T-cell expressed and secreted) and eotaxin-1, are thought to play important roles in the induction of eosinophilic airway inflammation, antigen-specific IgE production, and AHR (4). Although airway inflammation and Th2 cytokines and chemokines are a cornerstone of asthma, the asthmatic response is complex, and the relative importance of some of these contributors may vary with stage or duration of disease.RANTES (CCL5) belongs to the CC chemokine family and induces leukocyte migration by binding to specific receptors in (Received in original form October 19, 2005 and in final form February 16, 2006 ) This work was supported by NIH grants HL-36577 and HL-61005 and EPA grant R825702.Correspondence and requests for reprints should be addressed to Erwin W. Gelfand, M.D., Department of Pediatrics, Nati...

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“…38 Since IFN-g had no effects on lung function, inhalation of IFN-g was has been evaluated as a possible means for preventing toxicity and enhancing the therapeutic effects of IFN-g administration. 39 Trials on indirect induction of Th1-type immune responses have also been carried out using animal models. The administration of various bacteria that can induce Th1-type immune responses has also been reported to inhibit the development of allergic-induced AHR.…”

Section: Il-4 Antagonistic Mutant Dna Inhibits Allergic Airway Inflammentioning

confidence: 99%

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

et al. 2003

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Interleukin 4 (IL-4) is essential for the switching of B cells to IgE antibody production and for the maturation of T helper (Th) cells toward the Th2 phenotype. These mechanisms are thought to play a crucial role in the pathogenesis of the allergic airway inflammation observed in asthma. In the present study, we examined the anti-inflammatory effects of DNA administration of murine IL-4 mutant Q116D/Y119D (IL-4 double mutant, IL-4DM), which binds to the IL-4 receptor a and is an antagonist for IL-4. Immunization of BALB/c mice with alum-adsorbed ovalbumin (OVA) followed by aspiration with aerosolized OVA resulted in the development of allergic airway inflammation. A single administration of IL-4DM DNA before the aerosolized OVA challenge protected the mice from the subsequent induction of allergic airway inflammation. Serum IgE level and extent of eosinophil infiltration in bronchoalveolar lavage (BAL) from IL-4DM DNA-administered mice were significantly lower than those in BAL from control plasmid-immunized mice. In our study, IL-4 or IL-4 mutants were not detected in sera from mice that had received a single administration of IL-4DM DNA. The results of this study provide evidence for the potential utility of IL-4 mutant antagonist DNA inoculation as an approach to gene therapy for asthma.

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Treatment of steroid‐dependent asthma with recombinant interferon‐gamma

Cited by 53 publications

References 25 publications

Immunoglobulin E-Dependent Regulation of the CCR3 Chemokine Receptor by Interferon-Gamma in Atopic Asthmatics

Immunoglobulin E-Dependent Regulation of the CCR3 Chemokine Receptor by Interferon-Gamma in Atopic Asthmatics

RANTES (CCL5) Regulates Airway Responsiveness after Repeated Allergen Challenge

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

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