Interleukin-1 receptor antagonist enhances islet engraftment without impacting serum levels of nitrite or osteopontin.

ABSTRACT

Interleukin-1beta (IL-1beta)-mediated early islet graft dysfunction and loss of islet mass can occur in different phylogenic types of islet transplantation. Large quantities of interleukin-1 receptor antagonist (IL-1RA) have been demonstrated to impede IL-1beta-mediated adverse effects on islet grafts in allo- and xenotransplantation. To clarify the influence of IL-1RA on early function and mass change, as well as long-term hypoglycemic effects of islet isografts, we studied streptozotocin-induced diabetic C57BL/6 mice infected with replication-defective adenovirus carrying the mouse IL-1RA cDNA gene. This vector increased the mean serum level of IL-1RA to 8 ng/mL, approximately three times greater than for mice receiving adenovirus carrying the beta-galactosidase (beta-Gal) gene. The blood glucose levels declined faster and the insulin content of the graft was significantly higher on day 10 following transplantation among mice receiving mIL-1RA gene than the controls. Nevertheless, the insulin content of the pancreatic remnant did not differ among mice in the IL-1RA, beta-Gal, and vehicle control groups. Serum levels of nitrite and osteopontin before and 3 days after islet transplantation did not differ considerably among the IL-1RA, beta-Gal, and vehicle groups. Compared with the beta-Gal group, temporary posttransplantation hyperglycemia was significantly shortened in the IL-1RA group mice. Removal of graft-bearing kidneys at 13 weeks following transplantation caused recurrence of hyperglycemia in all treated diabetic mice. The insulin content of pancreatic remnants removed at 15 weeks following transplantation was similar in the IL-1RA and beta-Gal groups. In conclusion, a mildly elevated serum concentration of IL-1RA protected and enhanced engraftment of islet isografts immediately after transplantation.