Inosine improves islet xenograft survival in immunocompetent diabetic mice.

Abstract

BACKGROUND: Inflammation is likely to be one of the factors responsible for early islet xenograft rejection. In this study, we have used a novel anti-inflammatory compound, inosine, to investigate the role of anti-inflammatory blockade in protecting rat pancreatic islets from xenograft rejection in diabetic balb/c mice. Inosine is a safe, naturally occurring purine, which appears to be nontoxic to humans, that has recently been shown to be an immunomodulator and anti-inflammatory agent. METHODS: For the transplantation model rat islets were placed under the renal capsule of streptozotocin diabetic balb/c mice and inosine -- (200 mg kg (-1) d (-1) or vehicle- treatment started the day of islet transplantation. RESULTS: In vehicle-treated mice rat islet xenografts were rejected within 2 - 11 days after transplantation. In contrast, in inosine-treated mice graft survival was markedly prolonged for up to 3 weeks. Furthermore, immunohistochemistry and morphometric analyses revealed that early islet graft infiltration by leukocytes (CD45(+)) is significantly reduced in the grafts from inosine-treated diabetic mice compared to vehicle-treated mice. As suggested from the graft survival data, inosine-treated mice had also a significantly better preserved beta-cell mass. CONCLUSIONS: These results clearly demonstrate that inosine treatment markedly reduced the early inflammatory reaction elicited by an islet xenograft and substantially prolongs the graft survival. Therefore, such an approach may form an important future component of therapeutic regimens applied in clinical islet xenotransplantation.