Purpose. Erythropoietin exerts anti-inflammatory, anti-apoptotic and cyto-protective effects in addition to its hematopoietic property. We have recently shown that ARA 290, a non-hematopoietic erythropoietin analogue, protected pancreatic islets from cytokine-induced damage and apoptosis and also ameliorated inflammatory responses through the inhibitory effects on macrophages, and results in engraftment of transplanted islets even with fewer syngeneic islet grafts. In this study, we further investigated the efficacy of ARA 290 on allogeneic pancreatic islet transplant (PITx) setting.

Methods. Immunomodulatory effects of ARA 290 were assessed by allogeneic mouse mixed lymphocyte culture (MLC). Isolated Balb/c (H-2^d) mouse pancreatic islets (3-400 islets) were transplanted into the liver of streptozotocin-induced diabetic C57BL/6N mice (H-2^b) via the portal vein. Recipient animals were given ARA 290 (120 [micro]g/kg) intraperitoneally just before and at 0, 6, and 24 hours and once per day up to 14 days after PITx. Animals without treatment were used as control. Blood glucose level was monitored, and graft survival was assessed.

Results. ARA 290 did not inhibit T cell proliferation nor IFN-γ production in allogeneic MLC. However, after the allogeneic PITx, ARA 290 treatment significantly prolonged median graft survival time to 19.3 days (n=6) as compared to those of untreated control group animals (1.4 days; n=5, p<0.01). One recipient animal in the ARA 290 treatment group maintained normoglycemia for more than 60 days. Of note, the ARA 290 treatment (sham-operation) alone did not cure diabetic mice (n=15).

Conclusion. ARA 290 did not modulate T cell mediated allogeneic response in MLC. However, in line with syngeneic PITx, ARA 290 significantly prolonged islet grafts survival following allogeneic PITx. With having anti-inflammatory and anti-apoptotic properties, ARA 290 may become a promising modality in clinical PITx.

CITATION INFORMATION: Watanabe M, Yao M, Andersson D, Brines M, Lundgren T, Kumagai-Braesch M. A Non-Hematopoietic Erythropoietin Analogue, ARA 290, Prolonged Allogeneic Pancreatic Islet Graft Survival in a Mouse Model. Am J Transplant. 2016;16 (suppl 3).

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