Successful long-term survival of pancreatic islet allografts in spontaneous or pancreatectomy-induced diabetes in dogs. Cyclosporine-induced immune unresponsiveness.
Nineteen pancreatectomized beagles and three spontaneously diabetic dogs were recipients of canine islet allografts from one or more unrelated donors. The islets, enriched 30-45-fold for endocrine cells and contained in a packed cell volume of less than 1.5 ml, were engrafted in the livers of recipient animals. Treatment of diabetic recipients with cyclosporine (CsA) was begun 3-5 days before islet transplantation and the initial dosage was adjusted to attain and maintain CsA serum trough levels between 400 and 600 ng/ml. Five dogs with CsA levels less than this (155 +/- 35 SEM ng/ml) at the time of transplantation promptly rejected their grafts, whereas rejection was encountered in only 1 of 17 diabetic animals in which the initial level exceeded 400 ng/ml. CsA was discontinued 30, 60, or 90 days after continuous therapy in 10 animals. Graft failure was observed 2 mo after stopping CsA in 1 animal and 5 mo in the other. Eight other islet allograft recipients have sustained fasting euglycemia for 7 and 8 mo in 2 and for at least 2 mo in the remainder. These results demonstrate that short-term CsA therapy prolongs survival of islet allografts and induces a state of immune unresponsiveness to islet alloantigens in dogs with experimental and spontaneous diabetes. The findings are unique for a nonrodent mammal and thus hold promise that similar results may be achieved for islet allografts of other mammalian species, including humans.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003524:Cyclosporins / Q000097:blood / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000628:therapy / Q000662:veterinary; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004283:Dog Diseases / Q000628:therapy; D004285:Dogs; D006085:Graft Survival / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D010180:Pancreatectomy; D013997:Time Factors
D001786:Blood Glucose; D003524:Cyclosporins