title: Attenuation of cross-talk between the complement and coagulation cascades by C5a blockade improves early outcomes after intraportal islet transplantation.
abstract: BACKGROUND
  Complement 5a factor (C5a) elicits a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. C5a is also linked to the coagulant activity in autoimmune diseases. Therefore, C5a most likely plays a crucial role in the instant blood-mediated inflammatory reaction.
  
  
  METHODS
  Intraportal transplantation of 2.5 islet equivalents/g of syngeneic rat islet grafts was performed in two groups of streptozotocin-induced diabetic rats: controls and C5a inhibitory peptide (C5aIP)-treated group.
  
  
  RESULTS
  The thrombin-antithrombin complex was significantly suppressed in the C5aIP group (P=0.003), and both the curative rate and the glucose tolerance were significantly improved in the C5aIP group (P<0.05 and P<0.005, respectively). Expression of tissue factor on granulocytes in recipient livers was up-regulated 1 h after islet infusion (P<0.0001), which was significantly suppressed by C5aIP (P<0.005). However, C5aIP was unable to regulate tissue factor expression on isolated islets. Furthermore, no differences were detected between the groups, regarding infiltration of CD11b-positive cells and deposition of C5b-9 on the islet grafts.
  
  
  CONCLUSIONS
  These data suggest that C5aIP attenuates cross-talk between the complement and coagulation cascades through suppressing up-regulation of tissue factor expression on leukocytes in recipient livers but not on islet grafts, a process leading to improvement in islet engraftment. Therefore, C5aIP in combination with conventional anticoagulants could be a strong candidate strategy to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation.
authors.affiliation: Division of Advanced Surgical Science and Technology, Tohoku University, Sendai, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tokodai
authors.forename: Masafumi
authors.initials: M
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakanishi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ogawa
authors.forename: Kazushige
authors.initials: K
authors.lastname: Satoh
authors.forename: Naoki
authors.initials: N
authors.lastname: Kawagishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sekiguchi
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.forename: Noriko
authors.initials: N
authors.lastname: Okada
authors.forename: Hidechika
authors.initials: H
authors.lastname: Okada
authors.forename: Susumu
authors.initials: S
authors.lastname: Satomi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D000991:Antithrombins / Q000276:immunology; D001777:Blood Coagulation / Q000502:physiology; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D006098:Granulocytes / Q000502:physiology; D007249:Inflammation / Q000517:prevention & control; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000502:physiology; D008099:Liver / Q000502:physiology; D011168:Portal System / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013917:Thrombin / Q000276:immunology; D013925:Thromboplastin / Q000235:genetics; D014185:Transplantation, Isogeneic / Q000502:physiology; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D015936:Complement C5a; D003165:Complement System Proteins; D013925:Thromboplastin; D013917:Thrombin