Alleviation of instant blood-mediated inflammatory reaction in autologous conditions through treatment of human islets with NF-κB inhibitors

Mazhar A. Kanak, Morihito Takita, Takeshi Itoh, Jeffrey A. Sorelle, Shyam Murali, Faisal Kunnathodi, Rauf Shahbazov, Michael C. Lawrence, Marlon F. Levy, Bashoo Naziruddin

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

BACKGROUND: The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) κB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-κB inhibitors affected IBMIR using an in vitro human autologous blood islet model. METHODS: Human islets were pretreated with or without NF-κB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry. RESULTS: Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-κB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups. CONCLUSIONS: A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-κB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.

Original languageEnglish (US)
Pages (from-to)578-584
Number of pages7
JournalTransplantation
Volume98
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Blood loop model
  • Human islets
  • Islet transplantation
  • Proinflammatory cytokine

ASJC Scopus subject areas

  • Transplantation

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