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

J Clin Invest. 2007 Dec;117(12):3868-78. doi: 10.1172/JCI33559.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Cells, Cultured
  • Cricetinae
  • Cytokines / immunology*
  • Disease Models, Animal
  • Humans
  • Hypersensitivity, Immediate / drug therapy*
  • Hypersensitivity, Immediate / immunology
  • Hypersensitivity, Immediate / pathology
  • Immunoglobulin E / immunology
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / immunology
  • Lung / immunology
  • Lung / pathology
  • Macaca mulatta
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • OX40 Ligand / antagonists & inhibitors*
  • OX40 Ligand / immunology
  • Receptors, OX40 / immunology
  • Skin / immunology
  • Skin / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology
  • Thymic Stromal Lymphopoietin
  • Tumor Necrosis Factor Inhibitors*
  • Tumor Necrosis Factors / immunology

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, OX40
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • Tnfrsf4 protein, mouse
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors
  • Immunoglobulin E
  • Thymic Stromal Lymphopoietin