IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice

Abstract

SUMMARYThe effect of an IL-1 receptor antagonist on recurrence of hyperglycaemia after syngeneic pancreatic islet transplantation to spontaneously diabetic female NOD mice was investigated. The transplanted animals were treated with either the receptor antagonist (8 . 0 mg/kg body weight per day for 12-14 days) or PBS, delivered by subcutaneously implanted osmotic pumps. In the control animals, a transient normoglycaemia was achieved, but hyperglycaemia was generally observed 6 days after islet transplantation. Administration of IL-1 receptor antagonist had a clear protective effect against recurrence of hyperglycaemia until day 14, but after cessation of drug delivery hyperglycaemia re-appeared. The results indicate that continuous administration of the IL-1 receptor antagonist can prevent recurrence of the diabetogenic process in NOD mice. IL-1 receptor antagonist may therefore become a useful adjuvant immunomodulating therapy after human islet transplantation in insulindependent diabetes mellitus.

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…Since IL-1β is the main inducer of MCP-1 by pancreatic islet cells in vitro [7,8], it is conceivable that increased IL-1β production is responsible for the early increase in graft MCP-1 expression. It is noteworthy that use of an IL-1 receptor antagonist prevents the recurrence of diabetes after syngeneic islet transplantation to diabetic NOD mice [69]. MCP-1 mRNA expression was also shown to be up-regulated in rat renal isografts [70] and the chemokine probably plays a role in the attraction of mononuclear cells to the graft.…”

Infection of intact human islets by a lentiviral vector

“…6,7 In addition, the inhibition of IL-1␤ by continuous systemic administration of IL-1Ra has been shown to block islet dysfunction, insulitis onset and diabetes in NOD mice. 8 Thus, as both a potentially therapeutic transgene and a secreted marker protein, stocks of lentiviral and adenoviral vectors expressing human interleukin-1 receptor antagonist protein were generated. Infection of 200 human islets with concentrated lentiviral IL-1Ra supernatant in triplicate in two separate experiments yielded 13.5 and 15.1 ng/ml IL-1Ra by ELISA in the medium 3 days later.…”

“…6,7 Treatment of NOD mice with interleukin 1 receptor antagonist protein following transplantation of syngeneic islets blocks autoimmune mediated rejection of the transplanted islets. 8 Thus the local inhibition of IL-1␤ by gene transfer of IL-1 inhibitors to islets could be used to block the onset of autoimmune-mediated islet dysfunction and apoptosis following transplantation.…”

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

“…IL1RN overproduction prevented the deleterious effects of IL-1β on beta cell function and apoptosis in cultured human islets [20]. In vivo, IL1RN administration prevented low-dose streptozotocin (STZ)-induced diabetes [21], and protected transplanted islets from allogeneic rejection [22] and autoimmune attack [23]. However, the potential effects of IL1RN on the initial non-specific beta cell damage after transplantation have not been determined.…”