Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth?

The survival of microencapsulated islet grafts is Limited, even if capsular overgrowth is restricted to a small percentage of the capsules. In search of processes other than overgrowth contributing to graft failure, we have s tudied the islets in non-overgrown capsules at several time points after al lotransplantation in the rat. All recipients of islet allografts became nor moglycemic. Grafts were retrieved at 4 and 8 weeks after implantation and a t 15.3 +/- 2.3 weeks postimplant, 2 weeks after the mean time period at whi ch graft failure occurred. Overgrowth of capsules was complete within 4 wee ks postimplant, and it was usually restricted to <10% of the capsules. Duri ng the first 4 weeks of implantation, 40% of the initial number of islets w as lost. Thereafter, we observed a decrease in function rather than in numb ers of islets, as illustrated by a decline in the ex vivo glucose-induced i nsulin response. At 4 and 8 weeks postimplant, beta-cell replication was 10 -fold higher in encapsulated islets than in islets in the normal pancreas, but these high replication rates were insufficient to prevent a progressive increase in the percentage of nonviable tissue in the islets. Necrosis and not apoptosis proved to be the major cause of cell death in the islets. Th e necrosis mainly occurred in the center of the islets, which indicates ins ufficient nutrition as a major causative factor. Our study demonstrates tha t not only capsular overgrowth but also an imbalance between beta-cell birt h and beta-cell death contributes to the failure of encapsulated islet graf ts. Our observations indicate that we should focus on finding or creating a transplantation site that, more than the unmodified peritoneal cavity, per mits for close contact between the blood and the encapsulated islet tissue.