title: Enhancement of islet engraftment and achievement of long-term islet allograft survival by Toll-like receptor 4 blockade.
abstract: BACKGROUND
  Toll-like receptors are key players in sterile inflammation phenomena and can link the innate and adaptive immune systems by enhancing graft immunogenicity. They are also considered mediators of types 1 and 2 diabetes development. The aim of the present study was to assess the role of Toll-like receptor-4 (TLR4) in mediating the inflammatory and immune responses to pancreatic islets, thereby promoting inflammatory destruction and immune rejection of islet grafts.
  
  
  METHODS
  Experiments were conducted in murine and human in vitro systems and in vivo murine islet transplant models, using species-specific anti-TLR4 monoclonal antibodies. In vitro, mixed lymphocyte-islet reaction experiments were performed to assess T-cell activation and proliferation. In vivo, both a syngeneic (B6-to-B6) marginal mass islet transplant model to assess the impact of TLR4 blockade on islet engraftment and an allogeneic (DBA1-to-B6) model were used.
  
  
  RESULTS
  In vitro TLR4 blockade decreased lipopolysaccharide-mediated β-cell apoptosis and T-cell activation and proliferation against allogeneic islets. In vivo, TLR4 blockade resulted in significantly better syngeneic marginal mass islet engraftment and in indefinite allogeneic islet graft survival. Tolerance was not observed because donor-specific skin graft rechallenge in nonrejecting animals resulted in rejection of both skin and islets, but without accelerated rejection as compared to naive animals.
  
  
  CONCLUSIONS
  Taken together, our data indicate that TLR4 blockade leads to a significant improvement of syngeneic islet engraftment and of allogeneic islet graft survival. A mechanism of graft accommodation with concurrent inhibition of donor-specific immune memory is likely to be involved.
authors.affiliation: 1 Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland. 2 Department of Endocrinology-Metabolisme and Diabetology-Nutrition, Jean Minjoz University Hospital, Besançon, France. 3 Division of Transplantation and Visceral Surgery, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland. 4 NovImmune, Plan-les-Ouates, Switzerland.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Yannick D
authors.initials: YD
authors.lastname: Muller
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lacotte
authors.forename: Géraldine
authors.initials: G
authors.lastname: Parnaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Borot
authors.forename: Raphaël P H
authors.initials: RP
authors.lastname: Meier
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lavallard
authors.forename: Benoît
authors.initials: B
authors.lastname: Bédat
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.forename: Philippe
authors.initials: P
authors.lastname: Morel
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4