title: Toll-like receptor 4 contributes to small intestine allograft rejection.
abstract: BACKGROUND
  Although outcomes for small intestine transplantation (SIT) have improved in recent years, allograft rejection rates remain among the highest of solid organ grafts. The high load of commensal bacteria in the small intestine may contribute through activation of the toll-like receptor (TLR) pathway. In this study, we examine the participation of TLR4 in acute allograft rejection in an orthotopic mouse model of SIT.
  
  
  METHODS
  Wild-type C57Bl/6 (H-2b) or TLR49(-/-) (H-2b) mice were transplanted with syngeneic (C57Bl/6), allogeneic (BALB/c; H-2d), or F1 (BALB/cxC57Bl/6; H-2d/b) vascularized, orthotopic small intestine grafts. Graft recipients were killed on days 2 to 6 posttransplant. Serum cytokines were measured by Luminex, and tissue was obtained for histology and quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  BALB/c grafts transplanted into C57Bl/6 recipients exhibited mixed inflammatory infiltrates, destruction of the mucosa, and significant apoptosis. TLR2 and TLR4 transcripts were modestly increased in syngeneic grafts on days 2 and 6 compared with native bowel, whereas TLR2 and TLR4 were significantly increased on days 2 and 6 in allogeneic grafts. Although fully mismatched and F1 grafts were rejected by C57Bl/6 recipients (mean survival time=8.2 and 9.3 days, respectively), graft survival was significantly prolonged in TLR4(-/-) recipients (mean survival time=10.6 and 14.3 days, respectively). Proinflammatory cytokines were markedly reduced in TLR4(-/-) graft recipients.
  
  
  CONCLUSIONS
  Small intestine graft survival is prolonged in the absence of TLR4, suggesting that gut flora associated with the graft may augment alloimmune responses through TLR4. Thus, the TLR pathway may be a novel therapeutic target for improving SIT allograft survival.
authors.affiliation: Department of Surgery/Division of Transplantation, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Sheri M
authors.initials: SM
authors.lastname: Krams
authors.forename: Mouer
authors.initials: M
authors.lastname: Wang
authors.forename: Ricardo O
authors.initials: RO
authors.lastname: Castillo
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Lori
authors.initials: L
authors.lastname: Phillips
authors.forename: John
authors.initials: J
authors.lastname: Higgins
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Esquivel
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Martinez
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4