Tumor necrosis factor (TNF) in inflammatory bowel disease: gene polymorphisms, animal models, and potential for anti-TNF therapy.
The inflammatory bowel diseases frequently require surgery because of intestinal complications. Animal models of inflammatory bowel disease, in particular those that histopathologically resemble Crohn's disease, are characterized by increased mucosal TNF production, and anti-TNF antibodies have shown efficacy in decreasing disease activity. These data have provided a rationale for immunotheraphy of Crohn's disease. Administration of anti-TNF antibodies to patients with Crohn's disease not responding to standard immunosuppressive treatment rapidly induced complete remissions, and healing of intestinal ulceration. A rapid reduction of circulating IL-6, CPR, and sPLA2 levels was observed in all patients, as well as a reduction of mucosal cells expressing RANTES and MIP-1. Short-term treatment with anti-TNF antibodies was not associated with significant toxicity, but results from long-term administration are still lacking. These data indicate that TNF is a pivotal and central inflammatory mediator in this disease. Further characterization of the precise mechanism of action of anti-TNF antibody therapy may further unravel the cause of immune dysregulation in Crohn's disease.
Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
P C
PC
Stokkers
L
L
Camoglio
S J
SJ
van Deventer
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D014409:Tumor Necrosis Factor-alpha