Therapeutic Dosing with Anti-Interleukin-13 Monoclonal Antibody Inhibits Asthma Progression in Mice

Abstract

In vivo models have demonstrated that interleukin-13 (IL-13) plays an important role in asthma; however, few studies have evaluated the effect of inhibition of IL-13 on established and persistent disease. In the present study, we have investigated the effect of a therapeutic dosing regimen with an anti-IL-13 monoclonal antibody (mAb) in a chronic mouse model of persistent asthma. BALB/c mice were sensitized to allergen [ovalbumin (OVA); on days 1 and 8] and challenged with OVA weekly from day 22. Anti-IL-13 mAb or vehicle dosing was initiated following two OVA challenges when disease was established. At this time, mice exhibited airway hyperresponsiveness (AHR), increased mucus production, inflammation, and initiation of subepithelial fibrosis compared with saline-challenged mice. Mice received four additional OVA challenges. Treatment with anti-IL-13 mAb inhibited AHR and prevented the further development of subepithelial fibrosis and progression of inflammation. Furthermore, mAb treatment reversed the mucus hyperplasia to basal levels. These effects were associated with an inhibition of cytokines, chemokines, and matrix metalloproteinase-9. These data demonstrate that neutralization of IL-13 can inhibit the progression of established disease in the presence of repeated allergen exposures.Asthma is characterized by the presence of reversible bronchoconstriction, increased sensitivity to specific and nonspecific bronchospasmic agents, and excessive mucus production. These clinical features are accompanied by an underlying pathology of inflammation and airway remodeling. The pathological changes are thought to contribute to the clinical symptoms of the disease (Fireman, 2003). Current therapies for asthma provide symptomatic control but do not halt the underlying disease, highlighting the unmet medical need. Patients are continually exposed to allergens or other bronchospasmic agents that may contribute to the maintenance or progression of persistent disease. Evidence to date suggests that interleukin-13 (IL-13) has an important role in asthma; it is associated with human disease, and preclinical models have demonstrated that it induces many of the features associated with human asthma.Elevated levels of IL-13 mRNA and protein (Huang et al., 1995) have been described in human disease pathogenesis, and polymorphisms in the IL-13 gene have been associated with asthma (Wills-Karp, 2000). Multiple studies have demonstrated that administration of recombinant murine (rm) IL-13 to the lungs of mice induces airway mucus hyperplasia, eosinophilia, and airway hyperresponsiveness (AHR) (Grunig et al., 1998;Wills-Karp et al., 1998;Singer et al., 2002;Kibe et al., 2003; Vargaftig and Singer, 2003a,b). These effects of IL-13 are reproduced in transgenic mouse systems where IL-13 overexpression is induced in a constitutive or inducible manner (Zhu et al., 1999Lanone et al., 2002). Chronic transgenic overexpression of IL-13 also induces subepithelial fibrosis and emphysema. Mice deficient in the IL-13 (and IL-4) signalin...

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production

“…IL-13 is a pleiotropic cytokine produced mainly by T cells and is critical for the development of airway hyperresponsiveness (AHR) associated with allergen exposure [18]. It has indeed been reported that treatment of mice with anti-IL-13 mAb inhibited AHR [19,20] and that Il-13-induced airway inflammation might involve a direct effect on airway smooth muscles [21]. Our results strongly suggest that IL-13 production is intrinsically different in the two mouse strains and accounts for the increased bronchial hyperresponsiveness in BALB/c mice.…”

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

“…In a mouse asthma model, treatment with an anti-IL-13 mAb prevented progression of inflammation by inhibiting the expression of cytokines and chemokines, such as TNF-␣ and MIP-1␣ (34,35). In addition, in endothelial cells, IL-13 induced NADPH oxidase activation and consequent production of ROS (36), possibly leading to oxidative damage and eventual cell death.…”

“…Whereas several studies have reported beneficial effects of IL-13, such as increased survival of mice in an experimental model of sepsis (33), harmful effects of IL-13 are also documented. For instance, in a mouse asthma model, allergic airway inflammation is inhibited by treatment with an anti-IL-13 mAb (34,35). Additionally, in endothelial cells, IL-13 induces ROS production via activation of NADPH oxidase (36).…”

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

“…In contrast, inhibition of IL-13, another Th 2 cytokine whose signal transduction pathway overlaps with that of IL-4, completely blocks airway hyperreactivity, subepithelial fibrosis and progression of inflammation in mouse asthma models. These effects were associated with an inhibition of MMP-9, neutralisation of IL-13 resulting in a reduction in total proteins MMP-9 levels in the lung tissue of mice (Yang et al, 2005).…”

“…In contrast, inhibition of IL-13, another Th 2 cytokine whose signal transduction pathway overlaps with that of IL-4, completely blocks airway hyperreactivity, subepithelial fibrosis and progression of inflammation in mouse asthma models. These effects were associated with an inhibition of MMP-9, neutralisation of IL-13 resulting in a reduction in total proteins MMP-9 levels in the lung tissue of mice (Yang et al, 2005).Some Th 2 cytokines contribute in a significant manner to pathology of asthma and other lung inflammatory diseases by interacting directly with MMPs or TIMPs resulting in an increase or decrease of their expression and activity. IL-4 decreased MMP-2 protein and mRNA levels in human bronchial fibroblasts in culture but did not alter TIMP-2 production leading to an increased TIMP-2/MMP-2 ratio.…”