Abstract: FR-PO677

Flt3 Inhibitor Attenuates Renal Injury in Adriamycin Nephropathy by Suppressing CD103+ DC-Mediated T Cell Activation

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Cao, Qi, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Chen, Titi, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Lee, Vincent W.S., The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Zheng, Guoping, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Wang, Yiping, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Harris, David C., The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
Background

In our previous study, CD103+ DCs were shown to play a pathogenic role via activation of CD8 T cells in Adriamycin nephropathy (AN), a model of focal segmental glomerulosclerosis. FMS-like tyrosine kinase 3 (Flt3) is a receptor which is highly and specifically expressed on tissue resident CD103+ DCs. To test the effect on renal injury of inhibition of Flt3 on CD103+ DCs, we used a selective Flt3 inhibitor (AC220) to treat mice with AN.

Methods

AN was induced in BALB/c mice, who were treated daily for 14 days with 10mg/kg AC220 or Vehicle (n=8/group) from day 7 after adriamycin, when AN was established. Renal functional and structural injury, as well as inflammatory cytokine expression and cell infiltration were assessed.

Results

The number of kidney CD103+ DCs, but not CD103- DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved renal function (creatinine clearance: 22.8±4.9 vs. 50.2±13.3 µl/min) and reduced structural renal injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines IL-1beta, IL-6 and TNF-a in kidney. AC220 treatment decreased infiltration of CD4 T cells, CD8 T cells and macrophages in kidney, and reduced inflammatory cytokine and cytotoxic molecule expression of kidney CD8 T cells in AN mice.

Conclusion

Flt3 inhibitor AC220 effectively reduced renal injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat chronic kidney disease.

Funding

  • Government Support - Non-U.S.