Attenuation of cross-talk between the complement and coagulation cascades by C5a blockade improves early outcomes after intraportal islet transplantation

Kazuaki Tokodai, Masafumi Goto, Akiko Inagaki, Wataru Nakanishi, Norihiko Ogawa, Kazushige Sato, Naoki Kawagishi, Satoshi Sekiguchi, Bo Nilsson, Noriko Okada, Hidechika Okada, Susumu Satomi

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1358-1365
Number of pages8
JournalTransplantation
Volume90
Issue number12
DOIs
Publication statusPublished - 2010 Dec 27

Keywords

  • C5a
  • Complement
  • Islets
  • Tissue factor
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

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