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

OX40 is a member of the TNFR superfamily, and is found predominantly on act ivated CD4-positive T cells. In vitro an OX40-IgG fusion protein inhibits m itogen- and Ag-driven proliferation and cytokine release by splenocytes and lymph node T cells. In contrast, an OX40 ligand-IgG fusion protein enhance d proliferative responses. In normal mice, OX40-positive cells are observed only in lymphoid tissues, including Peyer's patches of the gut. In mice wi th hapten-induced colitis or IL-2 knockout mice with spontaneous colitis, O X40-positive cells are found infiltrating the lamina propria. Administratio n 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 b owel disease. This was evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha, IL-1, IL-12, and IFN-gamma; and a reduct ion in the T cell infiltrate. Targeting OX40 therefore shows considerable p romise as a new strategy to inhibit ongoing T cell reactions in the gut.