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 2

Agonistic anti-CD137 mAb prevents AHR and eosinophilic airway inflammation in OVA-immunized BALB/c mice.

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Agonistic anti-CD137 mAb prevents AHR and eosinophilic airway inflammati...
(A) Methacholine-induced AHR was measured 17 and 45 days after antibody injection. At both time points, anti-CD137 mAb completely inhibited AHR in OVA-immunized mice (measured by enhanced pause [Penh]). (B) The increased cell number in the BAL fluid of OVA-immunized mice was almost completely abrogated by anti-CD137 mAb at both observation points. (C) Lung tissues from BALB/c mice sacrificed on day 46 (H&E; magnification, ×100) revealed dense peribronchiolar mononuclear cell infiltrates consisting mainly of lymphocytes and eosinophils in the OVA-immunized group. Inflammation was strongly reduced by anti-CD137 mAb. (D) Computer-based quantification of lung inflammation clearly demonstrated the significant antiinflammatory effect of anti-CD137 mAb. (E) PAS-stained lung sections (magnification, ×100) revealed mucus hypersecretion in OVA-immunized mice compared with controls, which was almost abrogated by anti-CD137 mAb. (F) Computer-based quantification of mucus production clearly verified inhibition of mucus production by anti-CD137 mAb. (G) Anti-CD137 mAb inhibited Th2 and induced Th1 cytokine production. This effect was still significant on day 46. (H) Anti-CD137 mAb almost completely inhibited proliferation of spleen cells of OVA-immunized BALB/c mice. (I) Anti-CD137 mAb significantly reduced OVA-specific IgE and IgG1 serum levels on days 18 and 46 in OVA-immunized mice. *P < 0.05, OVA plus anti-CD137 mAb versus OVA plus control antibody by Student’s t test. (A–F) n ≥ 9 animals per group and data point; data are expressed as mean ± SEM from 3 independent experiments. (G–I) n ≥ 4 animals per group; here representative results from 1 of 3 experiments are shown.