Xenogeneic islet transplantation of microencapsulated porcine islets for therapy of type I diabetes: long-term normoglycemia in STZ-diabetic rats without immunosuppression.

PURPOSE

Rejection and possible infection with porcine pathogens are obstacles in clinical xenogeneic transplantation of porcine pancreatic islets (PPI) to treat diabetic patients. A solution to this problem could be microencapsulation of the PPI. However, isolation and microencapsulation are highly demanding tasks with considerable risks of damaging the PPI. Thus, it is not surprising that the long-term function (>200 days) of microencapsulated PPI (mPPI), transplanted to diabetic rats, has been observed only in a few cases.

METHODS

Diabetes was induced in Wistar rats with streptozotozin (STZ 60 mg/kg body weight). Animals with consecutive blood glucose levels >300 mg/dl for more than 2 days were considered diabetic. PPI were isolated from brain-dead hybrid pigs (age 6-7 months or 2-3 years) using the Ricordi-technique and Liberase(PI). After in vitro culture PPI were microencapsulated with highly purified barium-alginate and 1,000 mPPI of 300-500 microm Ø were transplanted under the left kidney capsule and/or into the peritoneal cavity of STZ-diabetic rats (n = 15) without immunosuppression. Daily, later weekly, blood glucose level and body-weight were measured.

RESULTS

mPPI showed normal glucose tolerance in vitro and also in vivo. Normoglycemia occurred between day 1 and 15 after transplantation. Four mPPI grafts functioned for more than 230 days, the longest now for >550 days. Three rats are currently normoglycemic for >40 days. Six rats lost xenograft function after 12-20 days, due to inflammatory reactions at the site of the grafts. Two xenografts failed to induce normoglycemia, because the capsules did not contain enough viable PPI.

CONCLUSIONS

Microencapsulated xenogeneic islets can induce long term normoglycemia in rats without immunosuppression. However, very often the grafts fail to control the blood glucose level adequately. The reasons for these failures are currently under investigation. Nevertheless, our results are very promising and might lead the way towards preclinical trials in non-human primates.