Regulation of T cell activation in vitro and in vivo by targeting the OX40-OX40 ligand interaction: amelioration of ongoing inflammatory bowel disease with an OX40-IgG fusion protein, but not with an OX40 ligand-IgG fusion protein

J Immunol. 1999 Jan 1;162(1):486-93.

Abstract

OX40 is a member of the TNFR superfamily, and is found predominantly on activated CD4-positive T cells. In vitro an OX40-IgG fusion protein inhibits mitogen- and Ag-driven proliferation and cytokine release by splenocytes and lymph node T cells. In contrast, an OX40 ligand-IgG fusion protein enhanced proliferative responses. In normal mice, OX40-positive cells are observed only in lymphoid tissues, including Peyer's patches of the gut. In mice with hapten-induced colitis or IL-2 knockout mice with spontaneous colitis, OX40-positive cells are found infiltrating the lamina propria. Administration of the OX40-IgG fusion protein to mice with ongoing colitis (but not the OX40 ligand-IgG) ameliorated disease in both mouse models of inflammatory bowel disease. This was evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha, IL-1, IL-12, and IFN-gamma; and a reduction in the T cell infiltrate. Targeting OX40 therefore shows considerable promise as a new strategy to inhibit ongoing T cell reactions in the gut.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / therapy
  • Concanavalin A / pharmacology
  • Cricetinae
  • Cytokines / biosynthesis
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Humans
  • Immunoglobulin G / genetics*
  • Immunoglobulin G / physiology
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / therapy
  • Injections, Intraperitoneal
  • Interleukin-2 / deficiency
  • Interleukin-2 / genetics
  • Ligands
  • Lymphocyte Activation / genetics*
  • Membrane Glycoproteins*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • OX40 Ligand
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / physiology
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / therapeutic use*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / physiology
  • Tumor Necrosis Factors

Substances

  • Cytokines
  • Epitopes, T-Lymphocyte
  • Immunoglobulin G
  • Interleukin-2
  • Ligands
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • Tnfrsf4 protein, mouse
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factors
  • Concanavalin A