IMMEDIATE DESTRUCTION OF XENOGENEIC ISLETS IN A PRIMATE MODEL

Transplantation of pancreatic islets from other species to man has the potential to cure diabetes, but whether such islet grafts will be sub ject to damage due to natural antibody-mediated hyperacute rejection i s unknown. We have examined the fate of islet xenografts in a recipien t with direct relevance to man, the cynomolgus monkey. Rabbit islets w ere prepared by an intraductal collagenase technique and incubated in neat rabbit, human, or cynomolgus serum, with and without heat inactiv ation, for up to 6 days. Islets were analyzed by flow cytometry for IG G and IGM binding, and scored for viability by supravital staining. Fo r in vivo studies, isolated islets were prepared from 4 New Zealand Wh ite rabbits (15-34x10(3) islets 70-85% purity) and transplanted beneat h the kidney capsule of normal cynomolgus monkeys after aggregation in either a rabbit or monkey blood clot. The tissue was retrieved at var ious times up to 4 days after transplantation and processed for light and electron microscopy. The results showed that rabbit islets bind he terophile antibody of both IGG and IGM subtypes. There was slow loss o f islet viability in vitro over 3 days of culture in neat human or cyn omolgus serum. Destruction of islets in vivo was more rapid with visib le damage within 6 hr associated with neutrophil infiltration. Subsequ ently, there was heavy mononuclear cell infiltration leading to total destruction within 4 days. The results suggest that immediate mechanis ms of graft rejection, possibly compliment and neutrophil mediated, re present a major barrier to islet xenotransplantation in humans.