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Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40.

Jember AG, Zuberi R, Liu FT, Croft M - J. Exp. Med. (2001)

Bottom Line: OX40 has been shown to participate in regulating clonal expansion and memory development of CD4 T cells and may synergize with CD28.Moreover, OX40(-/)- mice exhibit diminished lung inflammation, including an 80-90% reduction in eosinophilia and mucus production, less goblet cell hyperplasia, and significantly attenuated airway hyperreactivity.These studies highlight the potential importance of OX40 in development of allergic asthma and suggest that targeting OX40 may prove useful therapeutically.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.

ABSTRACT
Asthma is thought to result from an abnormal expansion of CD4 T cells reactive with airborne allergens, and pathology is controlled by several cytokines of the T helper type 2 (Th2) family. The exact molecules which are involved in generating allergen-reactive T cells are not clear. Studies with blocking reagents or knockout animals have shown that the CD28/B7 interaction partially controls development of allergic asthma in mouse models, but may not be the sole molecule involved. In this report, we have investigated the role of the tumor necrosis factor receptor family member OX40 in allergic inflammation using OX40-deficient mice. OX40 has been shown to participate in regulating clonal expansion and memory development of CD4 T cells and may synergize with CD28. Our studies demonstrate that OX40(-/)- mice, primed with the model allergen ovalbumin and challenged through the airways with aerosolized antigen, are severely impaired in their ability to generate a Th2 response characterized by high levels of interleukin (IL)-5, IL-4, and immunoglobulin E. Moreover, OX40(-/)- mice exhibit diminished lung inflammation, including an 80-90% reduction in eosinophilia and mucus production, less goblet cell hyperplasia, and significantly attenuated airway hyperreactivity. These studies highlight the potential importance of OX40 in development of allergic asthma and suggest that targeting OX40 may prove useful therapeutically.

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Lung inflammatory infiltrates, goblet cell hyperplasia, and mucus production are reduced in OX40-deficient animals. Wt and OX40−/− mice were immunized and challenged with OVA as in the legend to Fig. 1, and lungs sectioned from mice that did not undergo BAL. Sections were stained with PAS. Original magnifications: Top, ×10; middle, ×20; bottom, ×40. Note that dark areas that are not nuclei represent mucus. Prominent mucus plugs and mucus positive goblet cells are visible in Wt bronchioles in the middle and bottom pictures.
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Figure 4: Lung inflammatory infiltrates, goblet cell hyperplasia, and mucus production are reduced in OX40-deficient animals. Wt and OX40−/− mice were immunized and challenged with OVA as in the legend to Fig. 1, and lungs sectioned from mice that did not undergo BAL. Sections were stained with PAS. Original magnifications: Top, ×10; middle, ×20; bottom, ×40. Note that dark areas that are not nuclei represent mucus. Prominent mucus plugs and mucus positive goblet cells are visible in Wt bronchioles in the middle and bottom pictures.

Mentions: The lungs from sensitized and challenged mice were removed immediately after testing for AHR and examined histologically by staining for cellular architecture around the bronchioles and for mucus production with PAS base. As seen in Fig. 4, whereas Wt mice had prominent cellular infiltration around the bronchioles, there was substantially less in the OX40-deficient mice, correlating with the reduced numbers of cells, particularly eosinophils, seen in the BAL fluid. Additionally, the extent of hyperplasia of the goblet cells was significantly lower in the absence of OX40, although compared with a mouse that was not challenged with antigen (not shown), some inflammation was still evident. A characteristic feature of asthma pathophysiology is mucus overproduction in the goblet cells and the appearance of mucus plugs within the bronchioles 3. There was a dramatic difference in mucus production, with ∼40% of goblet cells staining strongly with PAS in Wt mice but only ∼5% staining strongly in OX40−/− animals (Fig. 3 b and 4). Additionally, mucus plugs within the bronchioles were common in lungs from Wt mice, whereas few were detectable in lungs from OX40 knockout mice (Fig. 4).


Development of allergic inflammation in a murine model of asthma is dependent on the costimulatory receptor OX40.

Jember AG, Zuberi R, Liu FT, Croft M - J. Exp. Med. (2001)

Lung inflammatory infiltrates, goblet cell hyperplasia, and mucus production are reduced in OX40-deficient animals. Wt and OX40−/− mice were immunized and challenged with OVA as in the legend to Fig. 1, and lungs sectioned from mice that did not undergo BAL. Sections were stained with PAS. Original magnifications: Top, ×10; middle, ×20; bottom, ×40. Note that dark areas that are not nuclei represent mucus. Prominent mucus plugs and mucus positive goblet cells are visible in Wt bronchioles in the middle and bottom pictures.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195923&req=5

Figure 4: Lung inflammatory infiltrates, goblet cell hyperplasia, and mucus production are reduced in OX40-deficient animals. Wt and OX40−/− mice were immunized and challenged with OVA as in the legend to Fig. 1, and lungs sectioned from mice that did not undergo BAL. Sections were stained with PAS. Original magnifications: Top, ×10; middle, ×20; bottom, ×40. Note that dark areas that are not nuclei represent mucus. Prominent mucus plugs and mucus positive goblet cells are visible in Wt bronchioles in the middle and bottom pictures.
Mentions: The lungs from sensitized and challenged mice were removed immediately after testing for AHR and examined histologically by staining for cellular architecture around the bronchioles and for mucus production with PAS base. As seen in Fig. 4, whereas Wt mice had prominent cellular infiltration around the bronchioles, there was substantially less in the OX40-deficient mice, correlating with the reduced numbers of cells, particularly eosinophils, seen in the BAL fluid. Additionally, the extent of hyperplasia of the goblet cells was significantly lower in the absence of OX40, although compared with a mouse that was not challenged with antigen (not shown), some inflammation was still evident. A characteristic feature of asthma pathophysiology is mucus overproduction in the goblet cells and the appearance of mucus plugs within the bronchioles 3. There was a dramatic difference in mucus production, with ∼40% of goblet cells staining strongly with PAS in Wt mice but only ∼5% staining strongly in OX40−/− animals (Fig. 3 b and 4). Additionally, mucus plugs within the bronchioles were common in lungs from Wt mice, whereas few were detectable in lungs from OX40 knockout mice (Fig. 4).

Bottom Line: OX40 has been shown to participate in regulating clonal expansion and memory development of CD4 T cells and may synergize with CD28.Moreover, OX40(-/)- mice exhibit diminished lung inflammation, including an 80-90% reduction in eosinophilia and mucus production, less goblet cell hyperplasia, and significantly attenuated airway hyperreactivity.These studies highlight the potential importance of OX40 in development of allergic asthma and suggest that targeting OX40 may prove useful therapeutically.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.

ABSTRACT
Asthma is thought to result from an abnormal expansion of CD4 T cells reactive with airborne allergens, and pathology is controlled by several cytokines of the T helper type 2 (Th2) family. The exact molecules which are involved in generating allergen-reactive T cells are not clear. Studies with blocking reagents or knockout animals have shown that the CD28/B7 interaction partially controls development of allergic asthma in mouse models, but may not be the sole molecule involved. In this report, we have investigated the role of the tumor necrosis factor receptor family member OX40 in allergic inflammation using OX40-deficient mice. OX40 has been shown to participate in regulating clonal expansion and memory development of CD4 T cells and may synergize with CD28. Our studies demonstrate that OX40(-/)- mice, primed with the model allergen ovalbumin and challenged through the airways with aerosolized antigen, are severely impaired in their ability to generate a Th2 response characterized by high levels of interleukin (IL)-5, IL-4, and immunoglobulin E. Moreover, OX40(-/)- mice exhibit diminished lung inflammation, including an 80-90% reduction in eosinophilia and mucus production, less goblet cell hyperplasia, and significantly attenuated airway hyperreactivity. These studies highlight the potential importance of OX40 in development of allergic asthma and suggest that targeting OX40 may prove useful therapeutically.

Show MeSH
Related in: MedlinePlus