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.
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