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  • Title: Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice.
    Author: Neurath MF, Fuss I, Pasparakis M, Alexopoulou L, Haralambous S, Meyer zum Büschenfelde KH, Strober W, Kollias G.
    Journal: Eur J Immunol; 1997 Jul; 27(7):1743-50. PubMed ID: 9247586.
    Abstract:
    Antibodies to tumor necrosis factor (TNF)-alpha have been recently proposed as effective treatment for patients with Crohn's disease. Here, we analyze the functional role of TNF-alpha in a mouse model of chronic intestinal inflammation induced by the hapten reagent 2,4,6,-trinitrobenzene sulfonic acid (TNBS) that mimics some characteristics of Crohn's disease in humans. Macrophage-enriched lamina propria (LP) mononuclear cells from mice with TNBS-induced colitis produced 10-30-fold higher levels of TNF-alpha mRNA and protein than cells from control mice. When mice with chronic colitis were treated by intraperitoneal injection of antibodies to TNF-alpha, an improvement of both the clinical and histopathologic signs of disease was found. Isolated macrophage-enriched LP cells from anti-TNF-alpha-treated mice produced strikingly less pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 in cell culture. The predominant role of TNF-alpha in the mouse TNBS-induced colitis model was further underlined by the finding that striking colonic inflammation and lethal pancolitis was induced in TNF-alpha-transgenic mice upon TNBS treatment. Conversely, no significant TNBS-induced colitis could be induced in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Complementation of TNF-alpha function in TNF-/- mice by the expression of a mouse TNF-alpha transgene was sufficient to reverse this effect. Taken together, the data provide direct evidence for a predominant role of TNF-alpha in a mouse model of chronic intestinal inflammation and encourage further clinical trials with antibodies to TNF-alpha for the treatment of patients with Crohn's disease.
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