Abstract
Therapy for asthma often includes the combined use of glucocorticoids and leukotriene receptor antagonists. The short-term, combined effects of these drugs on cytokine secretion and lymphocyte proliferation are ill-defined. The aim of this study was to analyze allergen and mitogen-induced cytokine secretion and lymphocyte proliferation in asthmatics and to determine the effect of combined therapy on these immune responses. Peripheral blood mononuclear cells were isolated from mild, persistent adult asthmatics (n = 28) and analyzed for cat allergen (Fel d 1) and mitogen (phytohemagglutinin) induced IL-13 and IFN-γ secretion and lymphocyte proliferation. Samples were analyzed before and after 10 days of therapy with oral zafirlukast, prednisone (0.5 mg/kg/day), and inhaled budesonide (1600 mcg/day). Both Fel d 1 and mitogen stimulation resulted in IL-13 and IFN-γ secretion. Combination drug therapy resulted in a significant decrease in allergen-induced IFN-γ secretion (p = 0.018) and allergen-specific lymphocyte proliferation (p = 0.02), while IL-13 secretion was unchanged (p = 0.109). This study indicates a role for Th1 cytokines as well as Th2 cytokines in the allergic response.
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Robinson D, Hamid Q, Ying S, et al.: Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression: Am Rev Respir Dis 148:401–406, 1993
Hoekstra MO, Hoekstra Y, De Reus D, et al.: Interleukin-4, interferon-gamma and interleukin-5 in peripheral blood of children with moderate atopic asthma. Clin Exp Allergy 27:1254–1260, 1997
Corrigan CJ, Kay AB: CD4 T-lymphocyte activation in acute severe asthma. Relationship to disease severity and atopic status. Am Rev Respir Dis 141:970–977, 1990
Cembrzynska-Nowak M, Szklarz E, Inglot AD, et al.: Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma. Am Rev Respir Dis 147:291–295, 1993
Krug N, Madden J, Redington AE, et al.: T-cell cytokine profile evaluated at the single cell level in BAL and blood in allergic asthma. Am J Respir Cell Mol Biol 14: 319–326, 1996
Gajewski TF, Joyce J, Fitch FW: Antiproliferative effect of IFN-gamma in immune regulation. III. Differential selection of TH1 and TH2 murine helper T lymphocyte clones using recombinant IL-2 and recombinant IFN-gamma. J Immunol 143:15–22, 1989
Coyle AJ, Tsuyuki S, Bertrand C, et al.: Mice lacking the IFN-gamma receptor have impaired ability to resolve a lung eosinophilic inflammatory response associated with a prolonged capacity of T cells to exhibit a Th2 cytokine profile. J Immunol 156:2680–2685, 1996
Hessel EM, Van Oosterhout AJ, Van Ark I, et al.: Development of airway hyperresponsiveness is dependent on interferon-gamma and independent of eosinophil infiltration. Am J Respir Cell Mol Biol 16:325–334, 1997
Randolph DA, Carruthers CJ, Szabo SJ, et al.: Modulation of airway inflammation by passive transfer of allergen-specific Th1 and Th2 cells in a mouse model of asthma. J Immunol 162:2375–2383, 1999
Hansen G, Berry G, DeKruyff RH, et al.: Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest 103:175–183, 1999
Wills-Karp M, Luyimbazi J, Xu X, et al.: Interleukin-13: central mediator of allergic asthma. Science 282:2258–2261, 1998
Cohn L, Tepper JS, Bottomly K: IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol 161:3813–3816, 1998
Yang M, Hogan SP, Henry PJ, et al.: Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin. Am J Respir Cell Mol Biol 25:522–530, 2001
Nagano Y, Kondo M, Tamaoki J, et al.: Peripheral blood Th1 and Th2 profile in patients with moderate asthma: effect of inhaled corticosteroid. J Asthma 39:247–253, 2002
Naseer T, Minshall EM, Leung DY, et al.: Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy. Am J Respir Crit Care Med 155(3):845–851, 1997
Bentley AM, Hamid Q, Robinson DS, et al.: Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med 153:551–556, 1996
Gemou-Engesaeth V, Bush A, Kay AB, et al.: Inhaled glucocorticoid therapy of childhood asthma is associated with reduced peripheral blood T cell activation and ‘Th2-type’ cytokine mRNA expression. Pediatrics 99:695–703, 1997
Braun CM, Huang SK, Bashian GG, et al.: Corticosteroid modulation of human, antigen-specific Th1 and Th2 responses. J Allergy Clin Immunol 100:400–407, 1997
Vargaftig BB, Singer M: Leukotrienes mediate murine bronchopulmonary hyperreactivity, inflammation, and part of mucosal metaplasia and tissue injury induced by recombinant murine interleukin-13. Am J Respir Cell Mol Biol 28:410–419, 2003
NAEPP Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health Publication: 17–20, 1997
Finn PW, Boudreau JO, He H, et al.: Children at risk for asthma: Home allergen levels, lymphocyte proliferation, and wheeze. J Allergy Clin Immunol 105:933–942, 2000
Lemanske RF, Jr, Sorkness CA, Mauger EA, et al.: Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 285:2594–2603, 2001
Drazen JM, Israel E, Boushey HA, et al.: Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 335:841–847, 1996
Lara-Marquez ML, Deykin A, Krinzman S, et al.: Analysis of T-cell activation after bronchial allergen challenge in patients with atopic asthma. J Allergy Clin Immunol 101:699–708, 1998
Aleksza M, Lukacs A, Antal-Szalmas P, et al.: Increased frequency of intracellular interleukin (IL)-13 and IL-10, but not IL-4, expressing CD4+ and CD8+ peripheral T cells of patients with atopic dermatitis. Br J Dermatol 147:1135–1141, 2002
Li Y, Simons FE, HayGlass KT: Environmental antigen-induced IL-13 responses are elevated among subjects with allergic rhinitis, are independent of IL-4, and are inhibited by endogenous IFN-gamma synthesis. J Immunol 161:7007–7014, 1998
Jenmalm MC, Van Snick J, Cormont F, et al.: Allergen-induced Th1 and Th2 cytokine secretion in relation to specific allergen sensitization and atopic symptoms in children. Clin Exp Allergy 31:1528–1535, 2001
Macaubas C, Sly PD, Burton P, et al.: Regulation of T-helper cell responses to inhalant allergen during early childhood. Clin Exp Allergy 29:1223–1231, 1999
Rawle FC, Mitchell EB, Platts-Mills TA: T cell responses to the major allergen from the house dust mite Dermatophagoides pteronyssinus, Antigen P1: comparison of patients with asthma, atopic dermatitis, and perennial rhinitis. J Immunol 133:195–201, 1984
Jeng KC, Liu MT, Wu CH, et al.: American cockroach Cr-PI allergen induces lymphocyte proliferation and cytokine production in atopic patients. Clin Exp Allergy 26:349–356, 1996
Blaher B, McCluskey J, Puy R, et al.: T cell response to grass pollen allergens: Correlation with skin test reactivity and serum IgE levels. Immunol Cell Biol 73:17–22, 1995
Sahid El-Radhi A, Hogg CL, Bungre JK, et al.: Effect of oral glucocorticoid treatment on serum inflammatory markers in acute asthma. Arch Dis Child 83:158–162, 2000
Leung DY, Martin RJ, Szefler SJ, et al.: Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 181: 33–40, 1995
Henderson WR, Jr, Tang LO, Chu SJ, et al.: A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med 165:108–116, 2002
Stelmach I, Jerzynska J, Kuna P: A randomized, double-blind trial of the effect of treatment with montelukast on bronchial hyperresponsiveness and serum eosinophilic cationic protein (ECP), soluble interleukin 2 receptor (sIL-2R), IL-4, and soluble intercellular adhesion molecule 1 (sICAM-1) in children with asthma. J Allergy Clin Immunol 109:257–263, 2002
Tohda Y, Nakahara H, Kubo H, et al.: Effects of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma. Clin Exp Allergy 29:1532–1536, 1999
Morita H, Takeda K, Yagita H, et al.: Immunosuppressive effect of leukotriene B(4) receptor antagonist in vitro. Biochem Biophys Res Commun 264:321–326, 1999
O’Sullivan S, Akveld M, Burke CM, et al.: Effect of the Addition of Montelukast to Inhaled Fluticasone Propionate on Airway Inflammation. Am J Respir Crit Care Med 167:745–750, 2003
Di Lorenzo G, Pacor ML, Pellitteri ME, et al.: In vitro effects of fluticasone propionate on IL-13 production by mitogen-stimulated lymphocytes. Mediat Inflamm 11:187–190, 2002
Visser MJ, Postma DS, Brand PL, et al.: Influence of different dosage schedules of inhaled fluticasone propionate on peripheral blood cytokine concentrations in childhood asthma. Clin Exp Allergy 32:1497–1503, 2002
Spahn JD, Landwehr LP, Nimmagadda S, et al.: Effects of glucocorticoids on lymphocyte activation in patients with steroid-sensitive and steroid-resistant asthma. J Allergy Clin Immunol 98:1073–1079, 1996
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Gibbons, F.K., Israel, E., Deykin, A. et al. The Combined Effects of Zafirlukast, Prednisone, and Inhaled Budesonide on IL-13 and IFN-γ Secretion. J Clin Immunol 25, 437–444 (2005). https://doi.org/10.1007/s10875-005-5625-6
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DOI: https://doi.org/10.1007/s10875-005-5625-6