Efficacy of soluble IL-4 receptor for the treatment of adults with asthma

doi:10.1067/mai.2001.115624

Journal of Allergy and Clinical Immunology

Volume 107, Issue 6, June 2001, Pages 963-970

https://doi.org/10.1067/mai.2001.115624 Get rights and content

Abstract

Background: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T_H2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. Objective: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. Methods: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. Results: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV₁ observed in the placebo group (–0.4 L and –13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (–0.1 L and –2% predicted; P = .05 over the 3-month treatment period). Daily patient-measured morning FEV₁ also demonstrated a significant decline in the placebo group (–0.5 L and –18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (–0.1 L and –4% predicted; P = .02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Δ 0.1) compared with that seen in the placebo group (Δ 1.4 over 1 month; P = .07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). Conclusion: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma. (J Allergy Clin Immunol 2001;107:963-70.)

Section snippets

Subjects

Subjects were identified from the population of 4 university- or community-based asthma clinics between May 1998 and September 1998. Approximately 150 subjects were screened, and 62 subjects were enrolled. Two subjects were previously enrolled in a study of IL-4R. Enrolled subjects were nonsmoking adults who met National Institutes of Health guidelines for moderate persistent asthma that was present for more than 1 year.²⁸ Patients were required to have used inhaled corticosteroids for more

Results

In this study design, with subjects whose asthma was poorly controlled at the initiation, it is expected that some patients would have increased asthma symptoms and be required to discontinue from the study because of the stringent safety guidelines. Patients were required to withdraw after a single exacerbation, which may have been expected to occur once during 12 weeks in this population with moderately severe disease, even in the absence of corticosteroid withdrawal. Most study

Discussion

This is the first study to demonstrate the potential clinical efficacy of a T_H2 inhibitor for the treatment of asthma. In this study we demonstrate that 3.0 mg of IL-4R nebulized weekly was significantly better than placebo in maintaining FEV₁ after corticosteroid discontinuation whether measured by means of clinic spirometry or with a portable spirometer twice daily. IL-4R also showed a trend to maintaining asthma symptom scores compared with placebo. The demonstrated ability to maintain lung

Acknowledgements

We thank Alexis Cunningham for her capable assistance in preparation of this manuscript.

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Citation Excerpt :
The Th2 lymphocytes can produce cytokines of interleukin (IL)-4, IL-5 and IL-13, which recruits multiple inflammatory cells, including macrophages, eosinophils and neutrophils, to the lesions [4]. Besides, it has been indicated that these Th2 cytokines contribute to immunoglobulin E (IgE) production, eosinophilia and airway hyperresponsiveness [5–7]. Thus, suppressing the inflammatory response could be an important strategy for the treatment of allergic asthma.
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^☆: *Other members of the IL-4R Asthma Study Group are Andrea Buchmeier, CCRC; Sue Fell, RN; Laura Fuller, RN; Christina Gallegos, CCRC; Patty Hall, RN; Yuni Kim, PhD; Peggy McHugh, MSN, RN; Sandy Vallery, RN; Roberta Hanna; and Larry A. Bauer, PharmD, RPh.

^☆☆: Reprint requests: Larry Borish, MD, Division of Allergy and Immunology, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

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Original Articles: Allergy, Rhinitis, Other Respiratory DiseasesEfficacy of soluble IL-4 receptor for the treatment of adults with asthma☆,☆☆

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgements

Immunity

J Pediatr

Hematol Oncol

J Allergy Clin Immunol

A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma

J Immunol

B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells

J Immunol

Suppression of in vivo polyclonal IgE responses by monoclonal antibody to the lymphokine B-cell stimulatory factor 1

Proc Natl Acad Sci U S A

Differential regulation of IgG1 and IgE synthesis by interleukin 4

J Exp Med

Nasal mast cells in perennial allergic rhinitis exhibit increased expression of the Fc epsilon RI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells

J Clin Invest

Human recombinant interleukin 4 induces Fc epsilon receptors (CD23) on normal human B lymphocytes

J Exp Med

Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes

J Exp Med

IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils

J Immunol

IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1

J Immunol

IL-4 controls the selective endothelium-driven transmigration of eosinophils from allergic individuals

J Immunol

IL-4 and TNF-alpha synergize to enhance eosinophil survival [abstract]

J Allergy Clin Immunol

A novel role for murine IL-4 in vivo: induction of MUC5AC gene expression and mucin hypersecretion

Am J Respir Cell Mol Biol

IL-4 directs the development of Th2-like helper effectors

J Immunol

IL-4 plays a dominant role in the differential development of Th0 into Th1 and Th2 cells

J Immunol

Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system

Proc Natl Acad Sci U S A

The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice

J Exp Med

Enhanced development of Th2-like primary CD4 effectors in response to sustained exposure to limited rIL-4 in vivo

J Immunol

Disruption of the murine IL-4 gene blocks Th2 cytokine responses

Nature

Original Articles: Allergy, Rhinitis, Other Respiratory Diseases
Efficacy of soluble IL-4 receptor for the treatment of adults with asthma☆,☆☆