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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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 5

Efficacy of α-OX40L mAb is mediated in part through depletion of OX40L-expressing DCs.

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Efficacy of α-OX40L mAb is mediated in part through depletion of OX40L-e...
(A) Experimental design to test depletion of DCs by α-OX40L mAb is shown. BALB/c mice (n = 6 per group) were administered TSLP and OVA–APC (or control PBS) intranasally on days 0, 1, and 2 and treated with mIgG2a, 4F5, or 4F5-DANA mAbs on days 0 and 2. On day 4, BALF, mediastinal lymph nodes, and lungs were harvested for analyses of DC numbers. Expression of OX40L on OVA+CD11C+MHC classII+ DCs in the mediastinal lymph nodes are shown for TSLP and OVA–APC-treated (B) or PBS-treated (C) animals. (D) Total numbers of OVA+CD11C+MHC classII+ DCs in the lung, mediastinal lymph nodes, and BALF are shown. All analyses were performed on live cells (propidium iodide excluded). Results are mean ± SD and are representative of 2 independent experiments. *P < 0.01 (Dunnett’s test).