Background: Islet graft loss caused by injurious inflammatory and innate immune responses, is a major obstacle in pancreatic islet transplantation (PIT). In this pathophysiology, the NF-κB plays a key role. Proteasome regulates the activation of NF-κB through degradation of the IκB. We herein tested our hypothesis that proteasome inhibition by bortezomib (BZB) suppresses early inflammatory responses and ameliorates islet engraftment.

Methods: C57BL/6 (B6) mice islets (200 IEQ) were transplanted into streptozotocin-induced diabetic B6 mice via the portal vein. Non-fasting blood glucose (BG), intraperitoneal glucose tolerance test (IPGTT), intrahepatic pro-inflammatory cytokine mRNA expression and histology were evaluated. In vitro effects of BZB were examined using RAW264.7 macrophages and isolated B6-primary islets.

Results: Only 9% (n=11) achieved normoglycemia in the untreated control PIT recipients. In contrast, a bolus BZB (0.5 mg/kg, IV) infusion 1 hr before PIT markedly improved the normoglycemic rate to 60% (n=10: Fig. 1A). BZB treatment significantly suppressed elevation of TNF-α, IL-1β and MIP-1β mRNA expression levels in the liver at 12 hrs after PIT (Fig 1B), and ameliorated the number of viable islets at the transplant-site. BG-AUC level upon IPGTT revealed a well-maintained islet graft function after the BZB treatment (BZB: 1028±375 vs control: 1411±269 mg/dl*hr, p<0.05). BZB inhibited LPS-induced TNF-α production from RAW264.7 cells as well as pro-inflammatory cytokine mRNA expressions in islets. Activated RAW246.7 cells reduced the number of cocultured primary islets at 24 hrs, whereas administration of BZB prevented islet death .

Conclusion: Proteasome inhibition by BZB just before PITx suppresses inflammatory responses and prevents early islet graft loss following PIT.

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