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 7

Anti-CD137 mAb induces CD4+ T cell anergy.

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Anti-CD137 mAb induces CD4+ T cell anergy. BALB/c mice w...
BALB/c mice were immunized with OVA in Alum i.p. on day 1 and treated with anti-CD137 mAb or control mAb on day 3. Mice were sacrificed 5 days later, and CD4+ T cells were isolated and restimulated in vitro with OVA. (A) Transfer of CD4+ T cells from OVA-immunized mice into SCID mice induced AHR in response to methacholine. This effect was abrogated when the OVA-immunized mice were treated with anti-CD137 mAb before cell transfer. Data are expressed as Penh (mean ± SEM; n ≥ 7 animals per group and data point, 2 independent experiments). (B) CD4+ T cells that were separated from OVA-immunized BALB/c mice proliferated in response to OVA. In contrast, CD4+ T cells separated from OVA-immunized BALB/c mice that had received anti-CD137 mAb did not proliferate. CD4+ T cells separated from OVA-immunized mice that had received anti-CD137 mAb did proliferate again when treated with IL-2. Data are expressed as mean cpm ± SEM; n ≥ 4 animals for each group. Representative results from 1 of 2 experiments are shown. (C) IL-2 abrogated anti-CD137 mAb–mediated inhibition of Th2 cytokine production in cell culture supernatants of OVA-immunized BALB/c mice. Data are expressed as mean ± SEM; n ≥ 4 animals for each group. Representative results from 1 of 2 experiments are shown. *P < 0.05, OVA versus OVA plus anti-CD137 mAb; #P < 0.05, OVA plus anti-CD137 mAb versus OVA plus anti-CD137 mAb plus IL-2 by Student’s t test.