Abstract: FR-PO1006

Effect of Conversion to Belatacept on Tacrolimus-Induced Diabetes Mellitus in Rats

Session Information

Category: Transplantation

  • 1701 Transplantation: Basic and Experimental

Author

  • Jin, Long, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
Background

Belatacept is a promising immunosuppressant for replacing calcineurin inhibitors (CNIs). However, its effect on CNIs-induced diabetes mellitus (DM) is not adequately studied. Therefore, we tested the effect of conversion to belatacept on tacrolimus-induced DM.

Methods

Two separate experiments performed. The first experiment was conducted to determine diabetogenicity of belatacept. We administered five doses of belatacept via tail vein injection at the weekly basis for four weeks. The second experiment was conversion study. After inducing tacrolimus-induced DM with three weeks treatment with tacrolimus (TAC), TAC was converted to belatacept for three additional weeks. The effect of belatacept on TAC-induced pancreatic islet dysfunction was evaluated. The influence of oxidative stress was evaluated by measuring markers of oxidative stress 8-OHdG and antioxidant enzyme maker of MnSOD in pancreas tissues. The effect of conversion to belatacept on macrophage infiltration and apoptosis were detected by ED-1 and caspase-3. We also measured cell viability AO/PI staining in isolated rat islets. Finally, the direct effect of belatacept on TAC-induced ROS production and cell viability in vitro were investigated.

Results

The first experiment showed that treatment with belatacept showed similar blood glucose level compares with VH group. However, there was no difference between the other groups and time course. From the first study, we found that 1 and 2 mg/kg of belatacept have a clinically relevant therapeutic level. As expected, conversion from TAC to belatacept groups improved TAC-induced pancreatic beta-cell dysfunction compared with the TAC and TAC withdrawal groups. TAC treatment increased the level of 8-OHdG and reduced the level of MnSOD, and conversion could recover this effect. Conversion to belatacept significantly decreased the level of ED-1 and caspase-3 compared with that in the TAC and TAC withdrawal groups. AO/PI staining showed that conversion to belatacept effectively decreased TAC-induced islet cell death. In vitro study revealed that belatacept treatment significantly decreased ROS production and cell viability compared with that reported with TAC alone

Conclusion

Our study indicated that conversion from TAC to belatacept is effective in improving TAC-induced DM, and belatacept has a protective effect against TAC-induced pancreatic islet injury.