Immunomodulation Techniques in a Pig-to-Rat Model of Xenoislet Transplantation to Prolong Graft Survival

Abstract

Pancreas allotransplantation can restore full metabolic control in patients with type I diabetes, but has several limitations. Pancreatic islet xenotransplantation (XiTx) is considered a reliable alternative. The aim of this study was to evaluate the effect of gamma-irradiation and a highly selective inducible nitric oxide synthase inhibitor (AE-ITU) in a model of pig-to-rat XiTx. Thirty-five female rats were made diabetic by intraperitoneal injection of streptozocin. Pig pancreatic islets were obtained by enzymatic digestion followed by purification on Ficoll gradients. Approximately 4,000 purified pig islet equivalents were placed under the left kidney capsule of the recipient rats. The rats were observed for 15 days and divided into five Groups (G): G1: controls, diabetic rats with no treatment; G2: XiTx; G3: XiTx after gamma-irradiation (20 Gy); G4: XiTx and administration of AE-ITU; G5: XiTx after gamma-irradiation and AE-ITU. Graft survival was defined as the maintenance of the glucose levels at less than 11 mmol/l and a normal response to i.v. glucose challenge. The graft survivals in Groups 2, 3, 4 and 5 were 4.1±1.8, 7.6±2.1, 7.6±2.4, and 10.9±2.3 days, respectively. The graft survival of G2 was significantly (p<0.05) lower than the other groups, and the graft survival of G5 was significantly higher in respect of both G3 and G4 (log-rank test: p=0.007). In conclusion, the combination of AE-ITU (to reduce the early inflammatory damage) and gamma-irradiation (to reduce the immunogenicity of the islets) may be considered an interesting option to prolong the euglycaemic period after XiTx.