Intrinsic AHR in IL-5 transgenic mice is dependent on CD4⁺cells and CD49d-mediated signaling

Abstract

. Intrinsic AHR in IL-5 transgenic mice is dependent on CD4 ϩ cells and CD49d-mediated signaling. Am J Physiol Lung Cell Mol Physiol 281: L653-L659, 2001.-Overexpression of interleukin (IL)-5 by the airway epithelium in mice using the rat CC10 promoter (NJ.1726 line) leads to several histopathologies characteristic of human asthma, including airway hyperreactivity (AHR). We investigated the contribution of B and T cells, as well as CD4 expression, to the development of AHR in IL-5 transgenic mice. NJ.1726 mice on a T cell or CD4 knockout background, but not on a B cell knockout background, lost intrinsic AHR. These effects occurred without decreases in IL-5 or eosinophils. We further investigated the contribution of ␣ 4-integrin signaling to the development of AHR in IL-5 transgenic mice through the administration of anti-CD49d (␣ 4-integrin) antibody (PS/2). Administration of PS/2 resulted in immediate (16-h) inhibition of AHR. The inhibition of AHR was not associated with a decrease in airway eosinophils. These studies demonstrate that, despite the presence of increased levels of IL-5 and eosinophils in the lungs of NJ.1726 mice, CD4 ϩ cells and ␣4-integrin signaling are necessary for the intrinsic AHR that develops in IL-5 transgenic mice.

A Causative Relationship Exists Between Eosinophils and the Development of Allergic Pulmonary Pathologies in the Mouse

“…Thus, IL-5 activities appear to be restricted to effects on eosinophils in this mouse model and not the additional cell types that have been implicated as potential targets of IL-5 (e.g., B cells (20), T cells (7,22,23), and airway smooth muscle (24)). Further support for this conclusion is provided by our demonstration that the selective ablation of eosinophils in the lung, without concurrent effects on T cell activities, also leads to the attenuation of airway mucus and the loss of AHR (40).…”

“…Thus, the loss of allergen-mediated pathologies in IL-5-deficient animals appears to link eosinophils to the development of these pulmonary pathologies. However, strategies targeting IL-5 to ablate eosinophils have inherent ambiguities because of activities this cytokine has on other cell types, including B cells (20), T cells (7,(21)(22)(23), and, potentially, airway smooth muscle activity (24). That is to say, is the loss of allergen-induced pathology in IL-5-deficient mice a consequence of effects on eosinophils and/or effects on these other IL-5 responsive cells?…”

Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma

“…However, increasing IL-5 levels can increase eosinophil CD11/CD18 binding (69), thus generating compensatory mechanisms for eosinophil infiltration independent of VCAM-1. Whether the decrease in AHR in the IL-5 transgenic mice was due to changes in eosinophil function or function of other airway cells in the presence of transgenic IL-5 was not reported (8). In clinical trials, anti-IL-5 did not block AHR (72), suggesting that either eosinophils were not required for AHR or that there were compensatory mechanisms as in the murine models.…”

“…However, this does not preclude stimulation of AHR by other mediators in asthma. In contrast to the IL-5 Ϫ/Ϫ mice, in IL-5 transgenic mice, administration of anti-␣4-integrin antibodies reduces AHR but did not reduce eosinophil infiltration (8). However, increasing IL-5 levels can increase eosinophil CD11/CD18 binding (69), thus generating compensatory mechanisms for eosinophil infiltration independent of VCAM-1.…”

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.…”