TRFK-5 Reverses Established Airway Eosinophilia But Not Established Hyperresponsiveness in a Murine Model of Chronic Asthma

Abstract

We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 +/- 29 eosinophils/microl BAL for DEX-treated mice versus 382 +/- 60 eosinophils/microl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 +/- 32 eosinophils/microl BAL versus 382 +/- 60 eosinophils/microl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-gamma) content of BAL fluid (0.49 +/- 0.09 ng/ml BAL fluid for DEX versus 1.50 +/- 0.24 ng/ml BAL fluid and 1.36 +/- 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.

The rise of the phoenix: the expanding role of the eosinophil in health and disease

“…Mathur et al showed that while anti-IL-5 could abolish established airway eosinophil infiltration, it could not abolish established AHR, a result compatible with human data (63). While this was a negative report on the importance of eosinophils, it could also suggest that if active eosinophilic inflammation has occurred in the airway, a period of healing or repair may be necessary before resolution of established AHR.…”

CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma

“…These results suggest that the therapeutic effect of CpG on eosinophilic inflammation, IgE levels, and AHR in this model may be a result of down-regulation of TH2 cytokine levels. Previous studies showed that anti-IL-4 or anti-IL-13 receptor Abs suppressed Ag-induced AHR, but not eosinophilic inflammation (32,33), and that anti-IL-5 Ab administered after Ag challenge suppressed eosinophilic inflammation but had little effect on AHR (34). Because natural allergic inflammatory reactions are mediated by a combination of Th2 cytokines, CpG-ODN administration may offer some advantage over therapeutic administration of single Abs against IL-4, IL5, or IL-13, or their receptors.…”

Airway Hyperresponsiveness, Late Allergic Response, and Eosinophilia Are Reversed with Mycobacterial Antigens in Ovalbumin-Presensitized Mice

“…However, there have been negative reports as well, suggesting that eosinophils are neither required nor sufficient to induce AHR (21). In other reports, treatment with mAb to IL-5 had no effect on the reversal of established AHR in mice (22) and humans (23) despite complete suppression of eosinophil accumulation of airway tissue. Further studies, therefore, are clearly warranted to understand the role of eosinophils in AHR.…”