Abstract: TH-OR121

Effect of Conversion to Belatacept on Tacrolimus-Induced Diabetes Mellitus

Session Information

Category: Transplantation

  • 1701 Transplantation: Basic and Experimental

Authors

  • Yang, Chul Woo, Seoul St. Mary's Hospital, Seoul, Korea (the Republic of)
  • Lim, Sun Woo, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Luo, Kang, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Shin, Yoo-Jin, The Catholic University of Korea, Seoul, Korea (the Republic of)
Background

The effect of belatacept conversion on tacrolimus (TAC)-induced diabetes mellitus (DM) is still undetermined. In the present study, we first tested the dose-dependent effect of belatacept on pancreatic islet function and viability in rats. Second, in an experimental model of TAC induced DM, TAC was switched to belatacept and parameters of glucose control were measured. In addition, the direct effect of belatacept on TAC-induced pancreatic islet cell injury was evaluated in vitro.

Methods

The first study was designed to evaluate whether belatacept has a diabetogenic effect in rats. We tested the dose-dependency of belatacept (0.25, 0.5, 1, 2, and 4 mg/kg) on pancreatic islet function and viability. The second study aimed to evaluate the effect of conversion from TAC to belatacept on pancreatic islet function in established TAC-induced DM. After the establishment of TAC-induced DM (three weeks), TAC was continued, withdrawn, or replaced by belatacept treatment (1 or 2 mg/kg). Rats were treated with vehicle or subcutaneous TAC daily, and belatacept was injected weekly via the tail vein. The effect of belatacept on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. The protective effect of belatacept was evaluated by measuring markers of oxidtive stress, apoptosis, and infiltrating macrophage. Reactive oxygen species production using MitoSOX red and cell death using Annexin V were also evaluated in INS-1 cells.

Results

Pancreatic islet function and islet cell death were not affected by any of the tested doses of belatacept. TAC withdrawal ameliorated pancreatic islet dysfunction compared with that in the group in which TAC treatment was continued, and conversion to belatacept further improved pancreatic islet function compared with that in the TAC withdrawal group. TAC-induced oxidative stress, apoptotic cell death, and infiltration of macrophages decreased with TAC withdrawal, and belatacept conversion further reduced those values. In an in vitro study, belatacept decreased TAC-induced pancreatic islet cell death and reactive oxygen species production.

Conclusion

The results of these studies suggest that conversion to belatacept is an effective approach to reduce TAC-induced DM. Moreover, belatacept has a protective effect against TAC-induced pancreatic islet injury.