The intermediacy of the spiro-pyrrolenine for biosynthesis of uro'gen Ill is supported by synthesis of both enantiomers of the spiro-lactam 6 followed by demonstration that cosynthetase, the enzyme which forms uro'gen Ill, is inhibited over twenty times more strongly by one enantiomer than by the other.

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-α, IL-1, IL-12, and IFN-γ; 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.

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