The immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients

doi:10.1067/mai.2001.119742

Journal of Allergy and Clinical Immunology

Volume 108, Issue 6, December 2001, Pages 915-917

https://doi.org/10.1067/mai.2001.119742 Get rights and content

Abstract

We have used an optimized, physiologically relevant in vitro assay system to show that in a concentration-dependent fashion the immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin), as well as the glucocorticoid dexamethasone, inhibit allergen-driven T-cell proliferation and IL-5 production in PBMCs from allergen-sensitized atopic asthmatic individuals at physiologic concentrations. This effect of cyclosporin A might at least partially account for its established clinical efficacy in sparing systemic glucocorticoid therapy while improving lung function in chronic, severe, glucocorticoid-dependent asthma. The data are also compatible with the hypothesis that the newer immunomodulatory drugs mycophenolate mofetil and sirolimus exert similar effects, perhaps with a more favorable benefit/risk ratio. (J Allergy Clin Immunol 2001;108:915-7.)

Section snippets

Subjects, materials, and methods

With Ethics Committee approval and written, informed consent, we obtained 100 mL of peripheral venous blood from 6 atopic, glucocorticoid-naive asthmatic patients sensitized to the allergen in the house dust mite Dermatophagoides pteronyssinus . Asthma was defined as a clear history of relevant symptoms, reversible airflow limitation (≥15% reversibility in FEV₁), and bronchial hyperreactivity (histamine provocative concentration causing a 20% fall in baseline FEV₁ ≤ 8 mg/mL). Sensitization to

Results

Results are summarized in Fig 1.

. Concentration-response curves for inhibition of allergen-induced T-cell proliferation and IL-5 production by dexamethasone, sirolimus, mycophenolate mofetil, and cyclosporin A. Data are expressed as the mean ± SEM (n = 6) percentages of the thymidine uptakes and supernatant IL-5 concentrations in the vehicle control (no drug) wells, which were 25,530 ± 2976 counts/min above background and 360.3 ± 36.3 pg/mL, respectively. P < .01 for all curves by 1-way

Discussion

We have demonstrated that cyclosporin A, sirolimus, and mycophenolate mofetil suppress IL-5 production and T-cell proliferation in an optimized in vitro assay system driven by specific allergen relevant to the clinical sensitivity of atopic asthmatic donors, in which IL-5 production correlates with the severity of the donors' asthma.⁴

Our findings on the inhibitory effects of dexamethasone and cyclosporin A on allergen-driven PBMC activation in this study extend previous reports that these drugs

References (10)

S Till et al.
IL-5 secretion by allergen-stimulated CD4+ T cells in primary culture: relationship to expression of allergic disease
J Allergy Clin Immunol
(1997)
A Haczku et al.
The effect of dexamethasone, cyclosporin and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma
J Allergy Clin Immunol
(1994)
M Humbert et al.
The relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma
Am J Respir Crit Care Med
(1997)
S Ying et al.
Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils and mast cells in bronchial biopsies obtained from atopic and non-atopic (intrinsic) asthmatics
J Immunol
(1997)
SJ Till et al.
Allergen-induced proliferation and IL-5 production by bronchoalveolar lavage and blood T cells following segmental allergen challenge
Am J Respir Crit Care Med
(1998)

There are more references available in the full text version of this article.

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^☆: Supported by an unrestricted grant from GlaxoSmithKline, UK, for the salary of N.P. and by a Clinician Scientist Fellowship from Medical Research Council, UK, awarded to C.C.

^☆☆: Reprint requests: C.J. Corrigan, MD, PhD, Department of Respiratory Medicine & Allergy, 5th Floor Thomas Guy House, Guy's Hospital, London SE1 9RT, United Kingdom.

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Brief CommunicationThe immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients☆,☆☆

Abstract

Section snippets

Subjects, materials, and methods

Results

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

The relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma

Am J Respir Crit Care Med

Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils and mast cells in bronchial biopsies obtained from atopic and non-atopic (intrinsic) asthmatics

J Immunol

Allergen-induced proliferation and IL-5 production by bronchoalveolar lavage and blood T cells following segmental allergen challenge

Am J Respir Crit Care Med

Brief Communication
The immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients☆,☆☆