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*
Department of Paediatric Gastroenterology, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, London, United Kingdom;
Department of Paediatrics, Chelsea and Westminster Hospital, London, United Kingdom; and
Department of Molecular Biology, Genentech, South San Francisco, CA 94402
Anti-TNF-
Ab therapy has been shown to be of benefit in the
treatment of active Crohn’s disease, but the tissue-injuring processes
in the gut mediated by TNF- that might be inhibited by neutralizing
Ab 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
ensues when lamina propria T cells in explant cultures of human fetal
small 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- in organ culture supernatants and a large
increase in TNF- mRNA transcripts. The addition of TNFR-IgG at the
onset of cultures greatly reduced PWM-induced tissue injury, without
inhibiting the increase in TNF- and IFN-
transcripts seen
following T cell activation. Mucosal injury in this model is mediated
by endogenously-produced matrix metalloproteinases (MMPs). When
TNFR-IgG was added to PWM-stimulated explants, there was a reduction in
MMPs in the explant culture supernatants, especially stromelysin-1.
Recombinant TNF- and IL-1ß added directly to mucosal mesenchymal
cell lines also caused an increase in MMP production, but only the
former was inhibited by the TNFR-IgG. These results suggest that one of
the ways in which TNF- causes tissue injury in the gut is by
stimulating mucosal mesenchymal cell to secrete matrix-degrading
metalloproteinases. Neutralization of this activity should help
maintain tissue integrity.
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