In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation
Dhaya Seshasayee, … , Sarah G. Hymowitz, Flavius Martin
Dhaya Seshasayee, … , Sarah G. Hymowitz, Flavius Martin
Published December 3, 2007
Citation Information: J Clin Invest. 2007;117(12):3868-3878. https://doi.org/10.1172/JCI33559.
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Research Article

In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation

Abstract

Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses.

Authors

Dhaya Seshasayee, Wyne P. Lee, Meijuan Zhou, Jean Shu, Eric Suto, Juan Zhang, Laurie Diehl, Cary D. Austin, Y. Gloria Meng, Martha Tan, Sherron L. Bullens, Stefan Seeber, Maria E. Fuentes, Aran F. Labrijn, Yvo M.F. Graus, Lisa A. Miller, Edward S. Schelegle, Dallas M. Hyde, Lawren C. Wu, Sarah G. Hymowitz, Flavius Martin

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Figure 3

α-OX40L mAb inhibits OVA-induced inflammation in the lung.

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α-OX40L mAb inhibits OVA-induced inflammation in the lung. (A) Experimen...
(A) Experimental design for an acute model of OVA-induced lung inflammation is shown. BALB/c mice (8 per group) were sensitized with OVA/alum or control alum alone on day 0 and challenged with 50 μg OVA administered intranasally daily on days 25–28. Mice were treated with 150 μg control mIgG2a, α-OX40L 4F5 Abs, or dexamethasone (2 mg/kg) intraperitoneally on days 26 and 27. Lungs were analyzed for inflammatory infiltrate (B), Th2 cytokines in the BAL (C), and serum antigen-specific IgE and IgG1 levels (D) on day 29. An increased number of OVA challenges model of lung inflammation is shown in E. BALB/c mice were sensitized with OVA/alum (or control alum alone) on day 0, boosted with OVA on day 14, challenged with OVA on days 49–60, and treated with mIgG2a or α-OX40L 4F5 antibodies intraperitoneally twice a week or 2 mg/kg dexamethasone daily, starting on day 53. Serum antigen-specific IgE and IgG1 levels were measured on day 74 (F). Results are mean ± SD. *P < 0.01 (Dunnett’s test).