LONG-TERM SURVIVAL AND STRAIN-SPECIFIC TOLERANCE INDUCTION IN RAT-TO-MOUSE NEONATAL ISLET XENOGRAFTS

These studies were designed to determine (1) if culture-isolated, neon atal rat islets are capable of inducing xenogeneic tolerance in mice a nd (2) whether this tolerance is species- or strain-specific. We attem pted to induce xenogeneic tolerance by transplanting culture-isolated neonatal FSH islets to 26 diabetic C57B1/6 recipients. These animals r eceived one injection of ALS at the time of transplant. Fifteen (58%) animals remained reversed by xenotransplant for >173 days. To assess t he development of strain or species-specific tolerance, 14 of the anim als bearing long-term surviving FSH grafts were divided into 3 treatme nt groups. Animals in group 1 were nephrectomized to remove the initia l graft and then retransplanted with uncultured, adult FSH islets; ani mals in group 2 were retransplanted with uncultured, adult FSH islets without nephrectomy; and group 3 animals were nephrectomized and retra nsplanted with uncultured, adult third-party islets (WF). In naive con trols, adult FSH islets were rejected in 9+/-2 days. The MST for adult FSH grafts transplanted to nephrectomized recipients was 104+/-54 day s, with 4 out of 5 (80%) surviving until sacrifice 90-171 days posttra nsplant. The MST for FSH grafts transplanted to nonnephrectomized reci pients was 120+/-70 days with 3 out of 4 (75%) surviving until sacrifi ce 143-154 days posttransplant. Thus, it appears that the initial neon atal FSH transplant induced the development of immune tolerance to hig hly immunogenic FSH islet tissue. In contrast, the MST for third-party adult WF grafts was 27+/-13 days compared with an MST of 36+/-24 days in naive controls. Thus, it appears that the xenogeneic tolerance ind uced by neonatal FSH islets was strain rather than species-specific. F actors such as the close evolutionary relationship between rats and mi ce, the neonatal condition of the initial graft, and its relative lack of donor APCs are included in a discussion of possible mechanisms of tolerance induction.