title: Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease.
abstract: Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors: Phyllissa
authors: P
authors: Schmiedlin-Ren
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors: Laura J
authors: LJ
authors: Reingold
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Florida Health System, Gainesville, Florida.
authors: Christopher S
authors: CS
authors: Broxson
authors: Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
authors: Ahren C
authors: AC
authors: Rittershaus
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors: Josh S
authors: JS
authors: Brudi
authors: Division of Gastroenterology, Department of Pediatrics and Communicable Diseases, University of Michigan Health System, Ann Arbor, Michigan; and.
authors: Jeremy
authors: J
authors: Adler
authors: Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
authors: Scott R
authors: SR
authors: Owens
authors: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Florida Health System, Gainesville, Florida ezimmer2@ufl.edu.
authors: Ellen M
authors: EM
authors: Zimmermann
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002432:Cecum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha
keywords: animal model; fibrosis; inflammatory bowel disease; stricture