Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice.
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.
Neurath
M F
MF
Laboratory of Immunology, I. Medical Clinic, University of Mainz, Germany.
Fuss
I
I
Pasparakis
M
M
Alexopoulou
L
L
Haralambous
S
S
Meyer zum Büschenfelde
K H
KH
Strober
W
W
Kollias
G
G
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid