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4-1BB stimulation inhibits allergen-specific immunoglobulin E production and airway hyper-reactivity but partially suppresses bronchial eosinophilic inflammation in a mouse asthma model

Authors

  • Y. S. Cho,

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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    • 1Y. S. Cho and B. Kwon contributed equally to this work.

  • B. Kwon,

    1. Department of Microbiology and Genetic Engineering and Immunomodulation Research Center, University of Ulsan, Ulsan, Korea,
    2. Xenotransplantation Research Center, College of Medicine, Seoul Nation University, Seoul, Korea
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    • 1Y. S. Cho and B. Kwon contributed equally to this work.

  • T.-H. Lee,

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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  • T.-B. Kim,

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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  • K.-A. Moon,

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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  • S. La,

    1. Department of Microbiology and Genetic Engineering and Immunomodulation Research Center, University of Ulsan, Ulsan, Korea,
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  • J. Lee,

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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  • S. D. Lee,

    1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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  • Y.-M. Oh,

    1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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  • H.-B. Moon

    1. Department of Medicine, Division of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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Hee-Bom Moon, Department of Medicine, Division of Allergy and Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul, Korea.
E-mail: hbmoon@amc.seoul.kr

Summary

Background 4-1BB, a member of the tumour necrosis factor receptor superfamily, functions as a co-stimulatory molecule. Recently, stimulation of the 4-1BB pathway was shown to suppress antigen-specific CD4+ T cell and subsequent T cell-dependent humoral immune responses.

Objective We examined the effect of agonistic anti-4-1BB monoclonal antibody (mAb) treatment on allergic asthma, in which allergen-specific type 2 helper T cells (Th2) have been shown to play an important role.

Methods BALB/c mice were systemically sensitized with intraperitoneal injections of ovalbumin (OVA) and alum on days 0 and 14, and then challenged with inhaled OVA on days 28, 29 and 30. In test groups, the agonistic anti-4-1BB mAb was administered at the time of initial systemic sensitization with OVA. On day 31, mice were challenged with inhaled methacholine, and enhanced pause was measured as an index of airway hyper-responsiveness (AHR). Levels of OVA-specific IgE in serum, and levels of various cytokines in bronchoalveolar lavage (BAL) fluids were measured. The severity of airway inflammation was determined by differential cell counts in BAL fluids and histopathologic lung analysis. To evaluate local immunity, we cultured lymphocytes from draining perihilar lymph nodes and evaluated the proliferative response to OVA and the levels of IL-5 in the culture supernatant. In addition, the functional mechanism of 4-1BB stimulation was evaluated in splenocytes obtained at day 7 after systemic OVA sensitization.

Results We found that treatment with the anti-4-1BB mAb significantly decreased AHR and the production of allergen-specific IgE. Bronchial inflammation, however, had only partially improved and the levels of IL-4 and IL-5 in BAL fluids showed only a small degree of reduction compared with the control Ig-treated mice. Thoracic lymphocytes from anti-4-1BB-treated mice showed significant suppression of OVA-induced proliferation and IL-5 production. In anti-4-1BB-treated mice, splenocytes exhibited poor proliferation and marked apoptosis 7 days after systemic OVA challenge.

Conclusion These results suggest that stimulation of the 4-1BB pathway effectively suppresses some features of allergic asthma, including allergen-specific IgE production and AHR, through deletion of allergen-specific Th2 cells. However, we found that bronchial allergic inflammation was not strictly mediated by suppression of the Th2 immune response in this murine model of asthma. Despite these somewhat contradictory effects, intervention in the 4-1BB pathway might provide a potential novel immunotherapeutic approach for treatment of allergic asthma.

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