CD137-mediated immunotherapy for allergic asthma
Tobias Polte, … , obert S. Mittler,, Gesine Hansen
Tobias Polte, … , obert S. Mittler,, Gesine Hansen
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):1025-1036. https://doi.org/10.1172/JCI23792.
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Research Article Immunology

CD137-mediated immunotherapy for allergic asthma

Abstract

The prevalence of asthma continues to increase. Asthma is caused by a Th2 cell–driven immune response. Its optimal treatment remains a challenge, and a sufficient immunotherapeutic approach to treating asthma has yet to be found. Using a murine asthma model, we show that a single injection of an anti-CD137 (4-1BB) mAb prevents the development of airway hyperreactivity, eosinophilic airway inflammation, excessive mucus production, and elevated IgE during the observation period of 7 weeks. Most importantly, even established disease is completely reversed by anti-CD137 mAb administration. The protection is associated with markedly reduced Th2 cytokine production and increased secretion of the Th1 cytokine IFN-γ. While B lymphocytes are partly depleted, the number of CD8+ T cells is increased. Blockade of IFN-γ and depletion of CD8+ T cells during treatment with anti-CD137 mAb reduces in part but does not abrogate the protective effect of CD137 mAb. In contrast, CD137 mAb–mediated CD4+ T cell anergy is critical for the observed effects, since transfer of CD4+ T cells from CD137 mAb–treated mice conveyed protection. These data demonstrate, for the first time to our knowledge, the capacity of anti-CD137 mAb to ameliorate allergic asthma, and they indicate CD137 as a possible target for therapeutic intervention in this disease.

Authors

Tobias Polte, Juergen Foell, Christoph Werner, Heinz-Gerd Hoymann, Armin Braun, Stefan Burdach, obert S. Mittler,, Gesine Hansen

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Figure 1

Immunization and antibody treatments.

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Immunization and antibody treatments. Prevention protocol: Mice were imm...
Prevention protocol: Mice were immunized with OVA i.p. on days 1 and 14, followed by intranasal (i.n.) OVA challenges on days 14–16, 28–30, and 42–44. Anti-CD137 mAbs were injected i.p. 1 day before the first OVA immunization. AHR was measured on days 17 and 45, and mice were sacrificed on day 18 (acute phase) or 46 (chronic phase). Reversal protocol I: Mice were immunized with OVA i.p. on day 1, followed by intranasal OVA challenges on days 8–10. To confirm the induction of AHR by OVA sensitization, AHR was measured the following day. Anti-CD137 mAb or control mAb was injected i.p. 12 hours after AHR measurement on day 11. Intranasal OVA challenge was repeated on days 15–17, and AHR was measured on day 18. Mice were sacrificed the following day. Reversal protocol II: Mice were immunized with OVA i.p. on day 1, followed by intranasal OVA challenges on days 8–10, 14–16, 21–23, and 29–31. To confirm the induction of AHR by OVA sensitization, AHR was measured the following day. Anti-CD137 mAb or control mAb was injected i.p. 12 hours after AHR measurement on day 32. Intranasal OVA challenge was repeated on days 39–41, and AHR was measured on day 42. Mice were sacrificed the following day (indicated by cross).