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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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 4

Therapeutic effect of anti-CD137 mAb in a chronic asthma model.

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Therapeutic effect of anti-CD137 mAb in a chronic asthma model. BALB/c m...
BALB/c mice were immunized with OVA on day 1 and challenged with OVA several times intranasally during the following 31 days. Lung function was measured on day 32. Anti-CD137 mAb was injected the same day, followed by further intranasal challenges with OVA (days 39–41). (A) OVA immunization resulted in methacholine-induced AHR as measured 1 day after the last intranasal OVA challenge (day 32). Injection of anti-CD137 mAb 12 hours after the first AHR measurement completely inhibited this already established AHR as demonstrated 10 days later. (B) Mice were sacrificed on day 43, and BAL was performed. Anti-CD137 mAb almost completely abrogated the total cell number in the BAL fluid of OVA-immunized BALB/c mice. (C) Anti-CD137 mAb reduced OVA-specific IgE serum levels in OVA-immunized BALB/c mice. (D) Anti-CD137 mAb converted an established Th2 to a Th1 cytokine response in culture supernatants of splenocytes and lung cells in OVA-immunized BALB/c mice. (E) Quantification of lung inflammation and mucus production by a computer-based image-analyzing program clearly demonstrated the inhibitory effect of anti-CD137 mAb. *P < 0.05, OVA plus anti-CD137 mAb versus OVA plus control antibody by Student’s t test. (a, b, and e) n ≥ 8 animals per group and data point; data are expressed as mean ± SEM from 2 independent experiments. (c and d) n ≥ 4 animals for each group; here representative results from 1 of 2 experiments are shown.