Transplantation of mouse pancreatic islets into primates--in vivo and in vitro evaluation.
Badet L., Titus TT., McShane P., Chang LW., Song Z., Ferguson DJ., Gray DW.
BACKGROUND: Islets transplanted from other species to man has the potential to cure diabetes but whether islets are subject to hyperacute rejection after xenotransplantation is contentious. We transplanted mouse pancreatic islets of mouse beneath the primate renal capsule and assessed natural xenoantibody binding, complement activation and cell lysis in vitro. METHODS: Freshly isolated mouse islets were transplanted in a blood clot under the renal capsule of cynolmogus monkeys. The graft was removed after 24 hr for histological and ultrastructural analysis. Freshly isolated mouse pancreatic islets were analyzed in vitro by immunohistochemistry for Gal(alpha1,3)Gal and Von Willebrand factor expression and for IgG, IgM, C3, C4, and C5b-9 binding after incubation in 100% human serum. Complement mediated cell lysis was evaluated by 51Cr release assays after incubation of islets for 4 hr in human serum, plasma, and lymph with and without added neutrophils. RESULTS: Mouse islets transplanted under the renal capsule of cynomolgus monkeys were destroyed within 24 hr by a process involving necrosis with neutrophil and mononuclear cell infiltration. Gal(alpha1,3)Gal was strongly positive on only 10% of islet cells. After islet incubation in 100% human serum before frozen section, human IgG and IgM, C3, C4, and C5b-9 was deposited on islets with increased intensity in the periphery. Measurement of 51Cr release from labeled fresh islets after four hours incubation in 100% human serum showed 17% lysis and was not changed by addition of neutrophils. CONCLUSION: These results indicate that mouse islets in a primate recipient undergo rapid destruction by a process that has features similar to hyperacute rejection in vascularized organs and we propose the same term be used.