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Histopathological Study of Intrahepatic Islets Transplanted in the Nonhuman Primate Model Using Edmonton Protocol Immunosuppression

Transplantation and Autoimmunity Branch (B.H., N.P., J.L., D.M.H.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Pathology Department (S.M.), Naval Medical Research Center, Silver Spring, Maryland 20910

Address all correspondence and requests for reprints to: David M. Harlan, M.D., Chief, Transplantation and Autoimmunity Branch, NIDDK, National Institutes of Health, Building 10, Room 11S210, Bethesda, Maryland 20892. E-mail: DavidMH{at}intra.niddk.nih.gov.

Abstract

While islet cell transplantation is a promising way to restore insulin independence to patients with type I diabetes mellitus, a detailed histological analysis of the transplanted, intraportal islets has not yet been reported. Rhesus macaques underwent total pancreatectomy, then had allogeneic isolated islets infused into their portal vein, followed by daclizumab, tacrolimus, and sirolimus to prevent islet rejection. Islets were evenly distributed among the liver lobes. Liver sections from a primate given allogeneic islets 5 d earlier did not display any islet capillary formation, whereas intrahepatic islets transplanted 30 and 90 d before euthanasia showed an abundant capillary supply. Localized hepatocellular glycogenosis was observed surrounding the islets in a primate with functioning islets 7 months post transplant. Liver sections from a primate that rejected islets transplanted 2 months prior displayed only islet remnants with prominent local lymphohistiocytic inflammation and an occasional capillary. We conclude that islets develop an abundant vascular supply within 30 d following transplant and because capillaries persist even following rejection, that the vascular cells are likely from the recipient. While transplanted islets were not vascularized early post transplant, the primates remained insulin independent. The long-term consequence of islets in the liver, marked by the glycogenosis, remains unknown and warrants further study.

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