title: Roles of Toll-like receptors in allogeneic islet transplantation.
abstract: BACKGROUND
  Toll-like receptors (TLRs) are involved in the rejection of solid organ allografts. However, the roles of TLRs in islets are still controversial. We investigated the roles of TLRs in donor islets together with those in recipients in allogeneic islet transplantation.
  
  
  METHODS
  To assess the roles of TLRs in either donor islets or recipients, allogeneic islet transplantation was performed using myeloid differentiation factor 88 (MyD88)-knockout (KO), TLR4-KO, or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-KO mice.
  
  
  RESULTS
  Both polyriboinosinic polyribocytidylic acid and lipopolysaccharide (LPS) stimulation induced the mRNA expression of regulated and normal T cell expressed and secreted, interferon-γ-inducible protein-10, monocyte chemotactic protein-1, interleukin-8, and inducible nitric oxide synthase in murine islets, whereas the induction was attenuated in TRIF-KO, interferon-β promoter stimulator-1-KO, and TLR4-KO mice. When islets from MyD88-KO, TLR4-KO, or TRIF-KO C57BL/6 mice were transplanted to BALB/c recipients, graft survival was not better than that of wild-type (WT) islets. However, the survival of the MyD88-KO islet allograft was significantly prolonged when combined with anti-CD40L. In parallel, LPS stimulation in donor islets interfered with anti-CD40L blockade-mediated long-term survival of islet allografts in TLR4-KO recipients. LPS stimulation increased the perigraft infiltration of both T cells and macrophages. Then again, when islets from WT BALB/c mice were transplanted to MyD88-KO, TRIF-KO, or WT C57BL/6 mice, there was no difference in graft survival, although some of the MyD88-KO recipients obtained long-term graft survival. However, anti-CD40L prolonged graft survival significantly in MyD88-KO recipients. The absence of MyD88 in either donors or recipients decreased the perigraft infiltration of inflammatory cells when combined with anti-CD40L.
  
  
  CONCLUSIONS
  TLRs in both donor islets and recipients are involved in islet allograft rejection.
authors.affiliation: Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Ro
authors.forename: Juho
authors.initials: J
authors.lastname: Hong
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Kim
authors.forename: Eun Won
authors.initials: EW
authors.lastname: Lee
authors.forename: Myung-Gyu
authors.initials: MG
authors.lastname: Kim
authors.forename: Kyu Hyun
authors.initials: KH
authors.lastname: Han
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Yeom
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Lee
authors.forename: Jong Cheol
authors.initials: JC
authors.lastname: Jeong
authors.forename: Kook-Hwan
authors.initials: KH
authors.lastname: Oh
authors.forename: Curie
authors.initials: C
authors.lastname: Ahn
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Yang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D054357:Chemokine CXCL10; D006084:Graft Rejection / Q000503:physiopathology*; D006085:Graft Survival / Q000502:physiology; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014019:Tissue Donors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014180:Transplantation; D014184:Transplantation, Homologous / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D016209:Interleukin-8; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D052247:Nitric Oxide Synthase Type II; D051197:Toll-Like Receptor 4; C491768:Ccl2 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse