Purpose. Pancreatic islet transplantation (PITx) is an attractive treatment option for type 1 diabetes patients. While pancreatic islets can successfully engraft after PITx a large numbers of islets are required, mainly because non-specific inflammatory reactions injure islet grafts and macrophage activation is deeply associated with these reactions. Erythropoietin exerts anti-inflammatory, anti-apoptotic and cyto-protective effects in addition to its hematopoietic property.

Methods. A non-haematopoietic erythropoietin analogue, ARA290 was used in this study. The effects of ARA290 on isolated pancreatic islets of C57BL/6 (H-2b) mice and on murine macrophage were investigated in an in vitro culture model. As a marginal PITx model, 175 islets were transplanted into the liver of STZ-induced diabetic mice (H-2b) via the portal vein. Recipients were given ARA 290 (120 ug/kg) intraperitoneally just before and at 0, 6 and 24 hours after PITx. Liver samples were obtained from islet-recipients at 12 hours after PITx, and expression levels of pro-inflammatory cytokines were assessed by real-time RT-PCR.

Results. ARA290 protected isolated islets from cytokine induced apoptosis. Pro-inflammatory cytokine secretion (IL-6, IL-12 and TNF-α) from activated macrophages was significantly inhibited by addition of ARA290. After the marginal PITx, ARA290 treatment significantly improved the normoglycemic rate (71.4%) when compared to those of vehicle treated control animals (16.7%; P<0.05). Blood glucose levels showed a normal pattern in ARA290-treated animals during glucose tolerance test. Upregulation of MCP-1, MIP-1β, IL-1β and IL-6 mRNA expression levels within the liver were significantly suppressed by ARA290 treatment.

Conclusions. ARA 290 ameliorated inflammatory response after PITx through the inhibitory effects on macrophages, and results in engraftment of transplanted islets even with fewer islet grafts.

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