Reduction of Antigen-induced Airway Hyperreactivity and Eosinophilia in ICAM-1-deficient Mice

Abstract

A murine model of asthma is described in which we examined the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of airway reactivity, pulmonary eosinophilia, and inflammation. We sensitized wild-type control [C57BL/6J, (+/+)] and ICAM-1 knockout [C57BL/6J-ICAM-1, (-/-)] mice to ovalbumin (OVA), and challenged them with OVA delivered by aerosol (OVA-OVA) to induce a phenotype consistent with an asthmatic response. Bronchial responsiveness to methacholine and counts of cell numbers and measurements of eosinophil content and cytokine levels in bronchoalveolar lavage fluid (BALF) were significantly attenuated in ICAM-1(-/-) mice as compared with (+/+) mice. We also showed that the absence of ICAM-1 had no significant affects on the production of serum IgE antibody, but did have an effect on ex vivo lymphocyte proliferation. Additionally, immunohistochemistry: (1) revealed increased staining for vascular cell adhesion molecule-1 (VCAM-1) after antigen challenge in the ICAM-1(-/-) mice but not in the ICAM-1(+/+) controls; and (2) confirmed the presence of alternatively spliced forms of ICAM-1 in the lungs of ICAM-1(-/-) mice. Thus, despite the availability of alternate adhesion pathways in ICAM-1(-/-) mice, the absence of ICAM-1 prevented eosinophils from entering the airways. In summary, we found that the ICAM-1 knockout mice exhibited a significantly inhibited response to aerosol antigen challenge for most of the parameters examined, and conclude that ICAM-1 is an important ligand mediating T-cell proliferation in response to antigen, eosinophil migration into the airways, and the development of airway hyperreactivity (AHR) in allergen-sensitized and -challenged mice.

Shifts in Lung Lymphocyte Profiles Correlate with the Sequential Development of Acute Allergic and Chronic Tolerant Stages in a Murine Asthma Model

“…In contrast, the maximal R L response to methacholine was significantly increased after 7 and 10 days of exposure (12.5 Ϯ 1.6 and 9.5 Ϯ 0.7 cm H 2 O/ml/second, respectively; P Ͻ 0.01 each) compared with the control response in naive animals (6.7 Ϯ 0.9 cm H 2 O/ml/second; Figure 4). Sensitivity to methacholine, as depicted by the interpolated concentration associated with R L equaling 270% of baseline, 23 increased nearly threefold with acute OVA challenge; however, sensitivity increased earlier than maximal responsiveness and returned to control values by 10 days of OVA aerosol challenge ( Figure 5). Aerosolized methacholine induced dose-dependent gas trapping in naive mice not exposed to OVA ( Figure 6).…”

“…23 OVA-immunized mice were exposed to 1% aerosolized OVA, 1 hour/day, for 1 to 10 days. Mice were studied 24 hours after the last inhalation and compared with naive mice.…”

Thy‐1 (CD90) regulates the extravasation of leukocytes during inflammation

“…For example, ICAM-1 À/À mice showed strongly decreased leukocyte infiltration in an OVA-induced inflammation model [31], as well as in a murine model of toluene diisocyanateinduced lung inflammation [32]. ICAM-2 À/À mice exhibited a delayed increase in eosinophil numbers in airway lumen and prolonged accumulation of eosinophils, compared to WT mice in an OVA immunization model [30].…”

Identification of antigenic epitopes on human allergens: studies with HLA transgenic mice.

“…Generation and use of transgenic and knockout mice for the multitude of mouse cytokines and their receptors (Borchers et al 2001;Cohn et al 2001;McMillan et al 2002;Wang et al 2001;Zhu et al 2001), cells (Chapoval et al 2001b;Corry et al 1998;MacLean et al 1999;Zuany-Amorim et al 1998), chemokine receptors (Lukacs et al 2001;Schuh et al 2002), costimulatory (Gonzalo et al 2001;Jember et al 2001;Mehlhop et al 2000), adhesion (Fiscus et al 2001;Wolyniec et al 1998), and signaling (Das et al 2001) molecules demonstrate new evidence for the role and significance of the immune system in the mechanisms of allergic tissue inflammation and airway hyperreactivity.…”