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, neonatal rat islets are capable of inducing xenogeneic tolerance in mice and (2) whether this tolerance is species- or strain-specific. We attempted to induce xenogeneic tolerance by transplanting culture-isolated neonatal FSH islets to 26 diabetic C57B1/6 recipients. These animals received one injection of ALS at the time of transplant. Fifteen (58%) animals remained reversed by xenotransplant for > 173 days. To assess the development of strain or species-specific tolerance, 14 of the animals bearing long-term surviving FSH grafts were divided into 3 treatment groups. Animals in group 1 were nephrectomized to remove the initial graft and then retransplanted with uncultured, adult FSH islets; animals in group 2 were retransplanted with uncultured, adult FSH islets without nephrectomy; and group 3 animals were nephrectomized and retransplanted with uncultured, adult third-party islets (WF). In naive controls, adult FSH islets were rejected in 9 +/- 2 days. The MST for adult FSH grafts transplanted to nephrectomized recipients was 104 +/- 54 days, with 4 out of 5 (80%) surviving until sacrifice 90-171 days posttransplant. The MST for FSH grafts transplanted to nonnephrectomized recipients was 120 +/- 70 days with 3 out of 4 (75%) surviving until sacrifice 143-154 days posttransplant. Thus, it appears that the initial neonatal FSH transplant induced the development of immune tolerance to highly 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 induced by neonatal FSH islets was strain rather than species-specific. Factors such as the close evolutionary relationship between rats and mice, 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.