In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation
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
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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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 2

α-mOX40L mAb blocks TSLP-induced inflammation in skin.

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α-mOX40L mAb blocks TSLP-induced inflammation in skin. BALB/c mice (n = ...
BALB/c mice (n = 5/group) were administered TSLP or control saline subcutaneously in the ear on days, 0, 2, 4, 7, and 9 and treated with 150 μg mIgG2a or α-mOX40L 4F5 mAb twice weekly, starting on day 0. (A) Ear thickness was measured every 3 days, and increase over baseline over the course of the study is shown. (B) Quantitative RT-PCR was performed on RNA isolated from ears of individual mice harvested terminally on day 21. Effects of α-OX40L mAb treatment on transcript levels of IL-4, IL-5, and IL-13 are shown with control mIgG2a set at a 100. Average Ct values for IL-4, IL-5, and IL-13 for the mIgG2a control group were 26.7, 24.2, and 22.4 respectively, and for the α-OX40L mAb treated group, were 29.4, 28.8, and 27.6 respectively. (C) Levels of total serum IgE on day 21 were measured by ELISA and are shown. Results are mean ± SD. *P < 0.01 (Dunnett’s test).