Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome

Abstract

Interleukin-1 receptor antagonist (IL1RN, also known as IL1RA) is a naturally occurring inhibitor of IL-1 action and its overproduction protects pancreatic islets from the deleterious effects of IL-1beta on beta cell replication, apoptosis and function. The aim of this study was to determine whether viral gene transfer of the Il1rn gene into rat islets ex vivo had a beneficial effect on the outcome of the graft. Streptozotocin-diabetic Lewis rats were syngeneically transplanted with 500 or 800 Ad-Il1rn-infected or uninfected islets. Islet grafts were collected on day 3, 10 or 28 after transplantation and beta cell apoptosis, replication, size and mass were determined. Animals transplanted with 500 islets remained hyperglycaemic throughout the follow-up, as expected. Beta cell replication increased in the Ad-Il1rn group on days 3, 10 and 28 after transplantation compared with normal pancreas. In uninfected islets, by contrast, beta cell replication was increased only on day 10. Beta cell apoptosis was increased in all transplanted groups; it was 25% lower in the Ad-Il1rn than in uninfected groups, but differences were not statistically significant. The initially transplanted beta cell mass was reduced on day 3, increasing subsequently in Ad-Il1rn grafts, but not in uninfected grafts. When 800 islets were transplanted, all animals grafted with Ad-Il1rn-infected islets, but only 40% of those transplanted with uninfected islets, achieved normoglycaemia 14 days after transplantation. Overproduction of IL1RN increased beta cell replication and mass of islet grafts and reduced the beta cell number required to achieve normoglycaemia.