525 A Proteasome Inhibitor, Bortezomib Prevents Pancreatic Islet Graft Loss After Transplantation
Tuesday November 17, 2015 from 15:30 to 17:00
Plenary Room 1

Hitoshi Ono, Japan

Gastroenterological surgery 1

Hokkaido University, Graduate school of Medicine


A Proteasome Inhibitor, Bortezomib Prevents Pancreatic Islet Graft Loss After Transplantation

Hitoshi Ono1, Yoh Asahi1, Tadashi Yoshida1, Yasuyuki Koshizuka1, Masaaki Watanabe1, Utano Tomaru2, Nozomi Kobayashi1, Shin Emoto1, Moto Fukai3, Tsuyoshi Shimamura4, Akinobu Taketomi1, Satoru Todo5, Kenichiro Yamashita3.

1Gastroenterological Surgery1, Hokkaido University, Sapporo, Japan; 2Pathology, Hokkaido University, Sapporo, Japan; 3Transplant Surgery, Hokkaido University, Sapporo, Japan; 4Organ Transplantation, Hokkaido University, Sapporo, Japan; 5St Mary's Hospital, Kurume, Japan

Background: Islet graft loss caused by inflammatory and innate immune-responses, is a major obstacle in pancreatic islet transplantation (PIT). We have previously shown that inhibition of NF-κB activation is an effective strategy to prevent graft loss after PIT; however, there is no specific inhibitor of NF-κB approved for clinical use. Proteasome degrades the inhibitory protein IκB and activates NF-κB. A Proteasome inhibitor, bortezomib (BZB) has been approved for treatment of multiple myeloma. The efficacy of BZB on early islet graft loss following PIT is unknown.
Aim: We examined whether proteasome inhibition by BZB suppresses early inflammatory responses and ameliorates islet engraftment.
Methods: 200 islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice via the portal vein. BZB was injected intravenously into recipient mice 1 h before PIT. Non-fasting blood glucose (BG), intraperitoneal glucose tolerance test (IPGTT), intrahepatic pro-inflammatory cytokine mRNA expression and liver histology were evaluated. The anti-inflammatory effect of BZB on mouse macrophages cell line and isolated primary islets were assessed in vitro.
Results: Only 9% (n=11) achieved normoglyceimia in the control mice. By contrast, BZB (0.5 mg/kg) treatment improved remarkably NGR (60%, n=10, p<0.05). This was accompanied with suppression of pro-inflammatory cytokine mRNA expressions such as TNF-α, IL-1β and MIP-1β in the liver. Histology revealed that BZB significantly preserved more variable islets, and the necrotic area of liver tissue was significantly decreased by BZB. Also, BZB treatment ameliorated the BG-AUC0-120 levels upon IPGTT (1028±375 mg/dl*hr) as compared to that of the control (1411±269 mg/dl*hr , p<0.05), which indicated that BZB improved the islet graft function. When isolated pancreatic 100 islets were coclultured with LPS-prestimulated RAW 246.7 cells for 24hrs, the number of islets reduced to  87.3 ± 6.2. In contrast, addition of BZB (10, 100, 1000 ng/ml) into the culture media inhibited islet death (91.4 ± 4.0, 99.1 ± 0.9, 99.5 ± 0.8). Treatment with BZB suppressed upregulation of TNF-α, MCP-1 and MIP-1β mRNA expression levels in both RAW 246.7 cells and cocultured islets.
Conclusion: A single bortezomib treatment just before PIT suppresses inflammatory responses at the transplant-site and prevents early islet graft loss.

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