title: Combination therapy of tacrolimus and infliximab reduces inflammatory response and dysmotility in experimental small bowel transplantation in rats.
abstract: BACKGROUND
  Intestinal transplantation initiates a functionally relevant inflammatory response by activation of resident macrophages within the muscularis associated with dysmotility. Infliximab is used successfully as a potent anti-inflammatory agent for the treatment of chronic inflammatory bowel diseases and as rescue therapy in acute steroid-resistant rejection in selected settings in clinical small bowel transplantation. We hypothesize that additional perioperative treatment with infliximab diminishes initiation of the inflammatory cascade and improves motility in small bowel grafts using a standard tacrolimus immunosuppressive protocol.
  
  
  METHODS
  Orthotopic intestinal transplantation was performed in rats. In two treatment groups (24/168 hr), infliximab was administered intravenously directly after reperfusion and tacrolimus was injected intramuscularly after transplantation and once a day. Two other treatment groups (24/168 hr) received standard immunosuppressive therapy with tacrolimus. Isogenic and allogenic transplanted vehicle-treated animals (24/168 hr) and native gut served as control.
  
  
  RESULTS
  Infliximab-treated grafts exhibited significantly less leukocyte infiltration at 24/168 hr after transplantation and at 168 hr significantly less apoptosis in the tunica muscularis compared with tacrolimus monotherapy. Additional infliximab treatment resulted in increased smooth muscle contractility (30%) after 24 hr compared with tacrolimus control.
  
  
  CONCLUSIONS
  Dysmotility of transplanted small bowel results from reperfusion injury and acute rejection. Additional perioperative treatment with infliximab reduces early unspecific inflammatory responses and complements immunosuppressive therapy with tacrolimus.
authors.affiliation: Department of Surgery, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pech
authors.forename: Jun
authors.initials: J
authors.lastname: Fujishiro
authors.forename: Tobias
authors.initials: T
authors.lastname: Finger
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Michael
authors.initials: M
authors.lastname: Praktiknjo
authors.forename: Kareem
authors.initials: K
authors.lastname: Abu-Elmagd
authors.forename: Martin
authors.initials: M
authors.lastname: von Websky
authors.forename: Marcus
authors.initials: M
authors.lastname: Overhaus
authors.forename: Joerg C
authors.initials: JC
authors.lastname: Kalff
authors.forename: Nico
authors.initials: N
authors.lastname: Schaefer
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004359:Drug Therapy, Combination; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006084:Graft Rejection / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007249:Inflammation / Q000517:prevention & control*; D000069285:Infliximab; D007421:Intestine, Small / Q000473:pathology / Q000637:transplantation*; D008264:Macrophages / Q000502:physiology; D020556:Neutrophil Infiltration; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D018925:Chemokines; D016207:Cytokines; D007166:Immunosuppressive Agents; D000069285:Infliximab; D016559:Tacrolimus