Suppression of Asthma-like Responses in Different Mouse Strains by Oral Tolerance

Abstract

In this study we examined the effect of oral antigen (Ag) administration on the development of experimental asthma in different mouse strains. We selected BALB/c, BP2, CBA/Ca interleukin (IL)-5 transgenic, and BALB/c T-cell receptor-delta-deficient mouse strains because they exhibit different aspects of the asthma syndrome. Mice exposed to 1% ovalbumin (OVA), dissolved in the drinking water for 5 consecutive days, became unresponsive to subsequent immunogenic OVA challenges. This regimen of OVA administration induced Ag-specific unresponsiveness in all mouse strains tested, including gammadelta-deficient mice that are said to be resistant to tolerance induction. The Ag-specific unresponsiveness was characterized by reduced (almost absent) airway eosinophilic inflammation, airway hyperreactivity, and mucus production; also by low levels of T helper (Th) 2-type cytokines in bronchoalveolar lavage fluid, and decreased immunoglobulin (Ig) G1 and IgE OVA-specific antibody production. The unresponsive state was not associated with increased levels of the suppressive cytokines IL-10 and transforming growth factor (TGF)-beta or with immune deviation toward the Th1 pathway due to increased levels of interferon-gamma and IL-12. Moreover, treatment with anti- TGF-beta antibodies did not abrogate oral tolerance. Oral Ag administration was quite effective in suppressing the development of key features of asthma when initiated after primary immunization (Day 0) or after booster (Day 7), but not after challenge (Day 14) when it increased allergic responses. Collectively, our findings show for the first time the beneficial and detrimental effects of oral Ag administration on the development of experimental asthma.

Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity

“…1). These results confirm that our protocol induces an intense eosinophilic inflammation (28). Intravenous LPS administration concomitantly with the second OVA challenge completely suppressed airway eosinophilia in the three mouse strains studied (Fig.…”

“…In our model, we found that immunized and OVA-challenged WT animals failed to develop a significant AHR to the spasmogen ␤-methacholine. Thus, to study AHR we used the BP2 mouse strain, which exhibits consistently larger AHR than most other mouse strains (28,34). As expected, immunized and OVA-challenged BP2 animals displayed an intense AHR response to ␤-methacholine (Fig.…”

“…Animals were immunized and challenged with OVA as previously described (28). Briefly, mice were immunized with 4 g of OVA (grade V)/1.6 mg of aluminum hydroxide gel in 0.4 ml of PBS on days 0 and 7.…”

“…The levels of cytokines (IL-4, IL-5, IL-13, and IFN-␥) in the BAL fluid were assessed by a sandwich kit ELISA according to the manufacturer's suggestion and as previously described (28). The following pairs of mAbs were used:11B11 and biotinylated BVD6 -24G for IL-4, TRFK5 and biotinylated TRFK4 for IL-5, and R4-6A2 and biotinylated XMG1.2 for IFN-␥, all purchased from BD PharMingen (San Diego, CA).…”

Splenic Dendritic Cells Induced by Oral Antigen Administration Are Important for the Transfer of Oral Tolerance in an Experimental Model of Asthma

“…In contrast, high-dose feeding of Ag induced clonal anergy and/or deletion that was not transferable (5)(6)(7)(8). Some studies have shown that high-or lowdose feeding of Ag prevents Th2-driven allergic inflammation such as bronchial eosinophilia (9 -11) and airway hyperresponsiveness (12,13). However, there have been few reports on whether feeding dose and regimen influence the effects of oral tolerance in Ag-induced lung inflammation in mice (14), which models certain aspects of human asthma.…”