title: Intestinal regeneration, residual function and immunological priming following rescue therapy after rat small bowel transplantation.
abstract: Clinical evidence suggests that recurrent acute cellular rejection (ACR) may trigger chronic rejection and impair outcome after intestinal transplantation. To test this hypothesis and clarify underlying molecular mechanisms, orthotopic/allogenic intestinal transplantation was performed in rats. ACR was allowed to occur in a MHC-disparate combination (BN-LEW) and two rescue strategies (FK506monotherapy vs. FK506+infliximab) were tested against continuous immunosuppression without ACR, with observation for 7/14 and 21 days after transplantation. Both, FK506 and FK506+infliximab rescue therapy reversed ACR and resulted in improved histology and less cellular infiltration. Proinflammatory cytokines and chemotactic mediators in the muscle layer were significantly reduced in FK506 treated groups. Increased levels of CD4, FOXP3 and IL-17 (mRNA) were observed with infliximab. Contractile function improved significantly after FK506 rescue therapy, with a slight benefit from additional infliximab, but did not reach nontransplanted controls. Fibrosis onset was detected in both rescue groups by Sirius-Red staining with concomitant increase of the fibrogenic mediator VEGF. Recovery from ACR could be attained by both rescue therapy regimens, progressing steadily after initiation of immunosuppression. Reversal of ACR, however, resulted in early stage graft fibrosis. Additional infliximab treatment may enhance physiological recovery of the muscle layer and enteric nervous system independent of inflammatory reactions.
authors.affiliation: Department of Surgery, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Pech
authors.forename: M
authors.initials: M
authors.lastname: von Websky
authors.forename: I
authors.initials: I
authors.lastname: Ohsawa
authors.forename: K
authors.initials: K
authors.lastname: Kitamura
authors.forename: M
authors.initials: M
authors.lastname: Praktiknjo
authors.forename: A
authors.initials: A
authors.lastname: Jafari
authors.forename: T O
authors.initials: TO
authors.lastname: Vilz
authors.forename: S
authors.initials: S
authors.lastname: Wehner
authors.forename: K
authors.initials: K
authors.lastname: Abu-Elmagd
authors.forename: J C
authors.initials: JC
authors.lastname: Kalff
authors.forename: N
authors.initials: N
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069285:Infliximab; D007421:Intestine, Small / Q000473:pathology / Q000502:physiology* / Q000637:transplantation*; D008264:Macrophages / Q000473:pathology; D008297:Male; D023421:Models, Animal; D009504:Neutrophils / Q000473:pathology; D016377:Organ Transplantation / Q000502:physiology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D016559:Tacrolimus