A P55 TNF RECEPTOR IMMUNOADHESIN PREVENTS T CELL-MEDIATED INTESTINAL INJURY BY INHIBITING MATRIX METALLOPROTEINASE PRODUCTION

Anti-TNF-alpha Ab therapy has been shown to be of benefit in the treat ment of active Crohn's disease, but the tissue-injuring processes in t he gut mediated by TNF-alpha that might be inhibited by neutralizing A b are unknown. In this work, we have used a p55 TNF receptor-human IgG fusion protein (TNFR-IgG) to prevent the severe mucosal injury that e nsues when lamina propria T cells in explant cultures of human fetal s mall intestine are directly activated with the lectin PWM. Following T cell activation and associated with mucosal injury, there is a marked elevation of soluble TNF-alpha in organ culture supernatants and a la rge increase in TNF-alpha mRNA transcripts, The addition of TNFR-IgG a t the onset of cultures greatly reduced PWM-induced tissue injury, wit hout inhibiting the increase in TNF-alpha and IFN-gamma transcripts se en following T cell activation, Mucosal injury in this model is mediat ed by endogenously-produced matrix metalloproteinases (MMPs). When TNF R-IgG was added to PWM-stimulated explants, there was a reduction in M MPs in the explant culture supernatants, especially stromelysin-1. Rec ombinant TNF-alpha and IL-1 beta added directly to mucosal mesenchymal cell lines also caused an increase in MMP production, but only the fo rmer was inhibited by the TNFR-IgG. These results suggest that one of the ways in which TNF-alpha causes tissue injury in the gut is by stim ulating mucosal mesenchymal cell to secrete matrix-degrading metallopr oteinases. Neutralization of this activity should help maintain tissue integrity.