Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives

Konstantinos Samitas, Vasiliki Delimpoura, Eleftherios Zervas, Mina Gaga, Konstantinos Samitas, Vasiliki Delimpoura, Eleftherios Zervas, Mina Gaga

Abstract

Asthma is a disorder of the airways involving various inflammatory cells and mediators and characterised by bronchial hyperresponsiveness, chronic inflammation and structural alterations in the airways, also known as remodelling. IgE is an important mediator of allergic reactions and has a central role in allergic asthma pathophysiology, as it is implicated in both the early and late phase allergic response. Moreover, clinical and mechanistic evidence has lately emerged, implicating IgE in the development of airway remodelling. The use of monoclonal antibodies targeting IgE, such as omalizumab, has proven very effective in improving respiratory symptoms and quality of life, while reducing asthma exacerbations, emergency room visits and the use of systemic corticosteroids in allergic severe asthma. These effects are believed to be mainly mediated by omalizumab's inhibitory effect on the initiation and further propagation of the allergic inflammation cascade. However, there is evidence to suggest that anti-IgE treatment remains effective long after it has been discontinued. In part, these findings could be attributed to the possible ameliorating effects of anti-IgE treatment on airway remodelling. In this review, we discuss recent findings supporting the notion that anti-IgE treatment modulates the complex immune responses that manifest clinically as asthma and ameliorates airway remodelling changes often observed in allergic severe asthma phenotypes.

Conflict of interest statement

Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com

Copyright ©ERS 2015.

Figures

FIGURE 1
FIGURE 1
Microphotographs (×20) of endobronchial biopsies from a) healthy control, b) mildly asthmatic and c) severe asthmatic airways demonstrating increased thickness of the basement membrane (haematoxylin–eosin stain) and goblet cell (GC) hyperplasia (periodic acid–Schiff stain) as asthma severity increases. EP: epithelium; RBMt: reticular basement membrane; Ang: angiogenesis. Scale bars=50 μm.

References

    1. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2014. Date last accessed: January 2015. Date last updated: May 2014.
    1. Holgate S, Casale T, Wenzel S, et al. . The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol 2005; 115: 459–465.
    1. Rabe KF, Calhoun WJ, Smith N, et al. . Can anti-IgE therapy prevent airway remodeling in allergic asthma? Allergy 2011; 66: 1142–1151.
    1. James A. Airway remodeling in asthma. Curr Opin Pulm Med 2005; 11: 1–6.
    1. Pascual RM, Peters SP. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview. J Allergy Clin Immunol 2005; 116: 477–486.
    1. James AL, Wenzel S. Clinical relevance of airway remodelling in airway diseases. Eur Respir J 2007; 30: 134–155.
    1. Hirota N, Martin JG. Mechanisms of airway remodeling. Chest 2013; 144: 1026–1032.
    1. Pain M, Bermudez O, Lacoste P, et al. . Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype. Eur Respir Rev 2014; 23: 118–130.
    1. Shifren A, Witt C, Christie C, et al. . Mechanisms of remodeling in asthmatic airways. J Allergy 2012; 2012: 316049.
    1. Humbert M, Busse W, Hanania NA, et al. . Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract 2014; 2: 525–536.
    1. Nopp A, Johansson SG, Adédoyin J, et al. . After 6 years with Xolair; a 3-year withdrawal follow-up. Allergy 2010; 65: 56–60.
    1. Solèr M. Omalizumab for severe allergic asthma: 7 years and open questions. Respiration 2014; 88: 158–161.
    1. Molimard M, Mala L, Bourdeix I, et al. . Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control. Respir Med 2014; 108: 571–576.
    1. Holowka D, Sil D, Torigoe C, et al. . Insights into immunoglobulin E receptor signaling from structurally defined ligands. Immunol Rev 2007; 217: 269–279.
    1. MacGlashan D, Jr. IgE receptor and signal transduction in mast cells and basophils. Curr Opin Immunol 2008; 20: 717–723.
    1. Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010; 125: Suppl. 2, S73–S80.
    1. Rosenwasser LJ, Meng J. Anti-CD23. Clin Rev Allergy Immunol 2005; 29: 61–72.
    1. Punnonen J, Aversa G, Cocks BG, et al. . Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 1993; 90: 3730–3734.
    1. Samitas K, Lötvall J, Bossios A. B cells: from early development to regulating allergic diseases. Arch Immunol Ther Exp 2010; 58: 209–225.
    1. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 2012; 18: 693–704.
    1. Mayr SI, Zuberi RI, Zhang M, et al. . IgE-dependent mast cell activation potentiates airway responses in murine asthma models. J Immunol 2002; 169: 2061–2068.
    1. Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 2004; 22: 789–815.
    1. Batra V, Musani AI, Hastie AT, et al. . Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on α-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 2004; 34: 437–444.
    1. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol 2003; 112: 252–262.
    1. Doherty T, Broide D. Cytokines and growth factors in airway remodeling in asthma. Curr Opin Immunol 2007; 19: 676–680.
    1. Zhu Z, Homer RJ, Wang Z, et al. . Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999; 103: 779–788.
    1. Kay AB, Phipps S, Robinson DS. A role for eosinophils in airway remodelling in asthma. Trends Immunol 2004; 25: 477–482.
    1. Samitas K, Zervas E, Vittorakis S, et al. . Osteopontin expression and relation to disease severity in human asthma. Eur Respir J 2011; 37: 331–341.
    1. Samitas K, Zervas E, Xanthou G, et al. . Osteopontin is increased in the bronchoalveolar lavage fluid and bronchial tissue of smoking asthmatics. Cytokine 2013; 61: 713–715.
    1. Gounni AS, Wellemans V, Yang J, et al. . Human airway smooth muscle cells express the high affinity receptor for IgE (FcεRI): a critical role of FcεRI in human airway smooth muscle cell function. J Immunol 2005; 175: 2613–2621.
    1. Roth M, Tamm M. The effects of omalizumab on IgE-induced cytokine synthesis by asthmatic airway smooth muscle cells. Ann Allergy Asthma Immunol 2010; 104: 152–160.
    1. Roth M, Zhong J, Zumkeller C, et al. . The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling. PLoS One 2013; 8: e56015.
    1. Redhu NS, Gounni AS. The high affinity IgE receptor (FcεRI) expression and function in airway smooth muscle. Pulm Pharmacol Ther 2013; 26: 86–94.
    1. Saglani S, Payne DN, Zhu J, et al. . Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007; 176: 858–864.
    1. Grainge CL, Lau LC, Ward JA, et al. . Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011; 364: 2006–2015.
    1. Takhar P, Corrigan CJ, Smurthwaite L, et al. . Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J Allergy Clin Immunol 2007; 119: 213–218.
    1. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med 2012; 18: 693–704.
    1. Campbell AM, Vachier I, Chanez P, et al. . Expression of the high-affinity receptor for IgE on bronchial epithelial cells of asthmatics. Am J Respir Cell Mol Biol 1998; 19: 92–97.
    1. Nakamura T, Kloetzer WS, Brams P, et al. . In vitro IgE inhibition in B cells by anti-CD23 monoclonal antibodies is functionally dependent on the immunoglobulin Fc domain. Int J Immunopharmacol 2000; 22: 131–141.
    1. Rosenwasser LJ, Busse WW, Lizambri RG, et al. . Allergic asthma and an anti-CD23 mAb (IDEC-152): results of a phase I, single-dose, dose-escalating clinical trial. J Allergy Clin Immunol 2003; 112: 563–570.
    1. Arm JP, Bottoli I, Skerjanec A, et al. . Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy 2014; 44: 1371–1385.
    1. Laffer S, Lupinek C, Rauter I, et al. . A high-affinity monoclonal anti-IgE antibody for depletion of IgE and IgE-bearing cells. Allergy 2008; 63: 695–702.
    1. Presta LG, Lahr SJ, Shields RL, et al. . Humanization of an antibody directed against IgE. J Immunol 1993; 151: 2623–2632.
    1. Chang TW. The pharmacological basis of anti-IgE therapy. Nat Biotechnol 2000; 18: 157–162.
    1. Chang TW, Shiung YY. Anti-IgE as a mast cell-stabilizing therapeutic agent. J Allergy Clin Immunol 2006; 117: 1203–1212.
    1. Chang TW, Wu PC, Hsu CL, et al. . Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol 2007; 93: 63–119.
    1. MacGlashan D, Jr. Therapeutic efficacy of omalizumab. J Allergy Clin Immunol 2009; 123: 114–115.
    1. MacGlashan DW, Jr, Bochner BS, Adelman DC, et al. . Down-regulation of FcεRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997; 158: 1438–1445.
    1. MacGlashan DW, Jr, Savage JH, Wood RA, et al. . Suppression of the basophil response to allergen during treatment with omalizumab is dependent on 2 competing factors. J Allergy Clin Immunol 2012; 130: 1130–1135.
    1. Prussin C, Griffith DT, Boesel KM, et al. . Omalizumab treatment downregulates dendritic cell FcεRI expression. J Allergy Clin Immunol 2003; 112: 1147–1154.
    1. Schroeder JT, Bieneman AP, Chichester KL, et al. . Decreases in human dendritic cell-dependent TH2-like responses after acute in vivo IgE neutralization. J Allergy Clin Immunol 2010; 125: 896–901.
    1. Chan MA, Gigliotti NM, Dotson AL, et al. . Omalizumab may decrease IgE synthesis by targeting membrane IgE+ human B cells. Clin Transl Allergy 2013; 3: 29.
    1. Lin H, Boesel KM, Griffith DT, et al. . Omalizumab rapidly decreases nasal allergic response and FcεRI on basophils. J Allergy Clin Immunol 2004; 113: 297–302.
    1. Eckman JA, Sterba PM, Kelly D, et al. . Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol 2010; 125: 889–895.
    1. Oliver JM, Tarleton CA, Gilmartin L, et al. . Reduced FcεRI-mediated release of asthma-promoting cytokines and chemokines from human basophils during omalizumab therapy. Int Arch Allergy Immunol 2010; 151: 275–284.
    1. Chanez P, Contin-Bordes C, Garcia G, et al. . Omalizumab-induced decrease of FcεRI expression in patients with severe allergic asthma. Respir Med 2010; 104: 1608–1617.
    1. Lommatzsch M, Korn S, Buhl R, et al. . Against all odds: anti-IgE for intrinsic asthma? Thorax 2014; 69: 94–96.
    1. Brusselle G, Michils A, Louis R, et al. . “Real-life” effectiveness of omalizumab in patients with severe persistent allergic asthma: the PERSIST study. Respir Med 2009; 103: 1633–1642.
    1. Buhl R. Anti-IgE: lessons from clinical trials in patients with severe allergic asthma symptomatic despite optimised therapy. Eur Respir Rev 2007; 16: 73–77.
    1. D'Amato G, Bucchioni E, Oldani V, et al. . Treating moderate-to-severe allergic asthma with a recombinant humanized anti-IgE monoclonal antibody (omalizumab). Treat Respir Med 2006; 5: 393–398.
    1. Humbert M, Beasley R, Ayres J, et al. . Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60: 309–316.
    1. Djukanović R, Wilson SJ, Kraft M, et al. . Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004; 170: 583–593.
    1. van Rensen EL, Evertse CE, van Schadewijk WA, et al. . Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy 2009; 64: 72–80.
    1. Riccio AM, Dal Negro RW, Micheletto C, et al. . Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol 2012; 25: 475–484.
    1. Hoshino M, Ohtawa J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration 2012; 83: 520–528.
    1. Tajiri T, Niimi A, Matsumoto H, et al. . Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study. Ann Allergy Asthma Immunol 2014; 113: 470–475.
    1. Takaku Y, Soma T, Nishihara F, et al. . Omalizumab attenuates airway inflammation and interleukin-5 production by mononuclear cells in patients with severe allergic asthma. Int Arch Allergy Immunol 2013; 161: Suppl. 2, 107–117.
    1. Huang YC, Leyko B, Frieri M. Effects of omalizumab and budesonide on markers of inflammation in human bronchial epithelial cells. Ann Allergy Asthma Immunol 2005; 95: 443–451.
    1. Zietkowski Z, Skiepko R, Tomasiak-Lozowska MM, et al. . Anti-IgE therapy with omalizumab decreases endothelin-1 in exhaled breath condensate of patients with severe persistent allergic asthma. Respiration 2010; 80: 534–542.
    1. Kang JY, Kim JW, Kim JS, et al. . Inhibitory effects of anti-immunoglobulin E antibodies on airway remodeling in a murine model of chronic asthma. J Asthma 2010; 47: 374–380.
    1. Tajiri T, Matsumoto H, Hiraumi H, et al. . Efficacy of omalizumab in eosinophilic chronic rhinosinusitis patients with asthma. Ann Allergy Asthma Immunol 2013; 110: 387–388.
    1. Mauri P, Riccio AM, Rossi R, et al. . Proteomics of bronchial biopsies: galectin-3 as a predictive biomarker of airway remodelling modulation in omalizumab-treated severe asthma patients. Immunol Lett 2014; 162: 2–10.
    1. Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discov 2012; 11: 958–972.
    1. Samitas K, Rådinger M, Bossios A. Current update on eosinophilic lung diseases and anti-IL-5 treatment. Recent Pat Antiinfect Drug Discov 2011; 6: 189–205.
    1. Long AA, Fish JE, Rahmaoui A, et al. . Baseline characteristics of patients enrolled in EXCELS: a cohort study. Ann Allergy Asthma Immunol 2009; 103: 212–219.
    1. Menzella F, Lusuardi M, Galeone C, et al. . Tailored therapy for severe asthma. Multidiscip Respir Med 2015; 10: 1.

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