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Kidney Week

Abstract: SA-OR042

Targeting CD103+ Dendritic Cells Using Flt3 Inhibitors for Treatment of Kidney Disease: Relevance to Human Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Harris, David C., Sydney Medical School - University of Sydney, Duffys Forest, New South Wales, Australia
  • Chen, Titi, The Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Cao, Qi, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia
  • Rao, Padmashree, Westmead Millenium Institute for Medical Research, Parramatta, New South Wales, Australia
  • Rogers, Natasha M., Westmead Institute for Medical Research, Westmead, New South Wales, Australia
  • Zheng, Guoping, The University of Sydney, Westmead, New South Wales, Australia
  • Lee, Vincent W.S., Westmead Hospital, Sydney, New South Wales, Australia
  • Yu, Hong, Westmead Institute for Medical Research Australia, Hornsby, New South Wales, Australia
  • Wang, Yiping, Centre for Transplantation and Renal Research, Westmead Millennium Institute, The University of Sydney, Westmead, New South Wales, Australia
Background

Whereas CD103+ dendritic cells (DCs) were previously considered to be a minor DC subset in kidney disease. we and others have proven that they have a major role. Flt3 is a receptor specifically expressed on tissue CD103+ DCs. Flt 3 inhibitors are currently used for cancer treatment.
In this study, our aims are
1. To examine CD141+ DCs (human homologue of mice CD103+ DCs) in human kidney diseases.
2. To explore the role of CD103+ DCs and therapeutic potential of targeting CD103+ DCs by repurposing Flt3 inhibitors in experimental kidney diseases.

Methods

For a human study, we included 294 patients who underwent kidney biopsies from 01/07/2016 to 01/04/2017. For animal experiments, we are using Adriamycin Nephropathy (AN), anti-GBM disease and ischemia reperfusion injury (IRI).

Results

In humans, the number and proportion of CD141+ DCs were significantly increased in proliferative glomerulonephritis and acute tubular necrosis (ATN). CD141+ DCs were found mainly in tubulointerstitium, except in lupus nephritis where they were also present in glomeruli. CD141+ DC numbers correlated with increasing severity of ATN (P<0.001) as well as increasing severity of fibrosis in IgA nephropathy (P=0.025), but not in diabetic nephropathy.

In murine AN, anti-GBM disease and IRI, the number and proportion of kidney CD103+ DCs were significantly increased. In AN, CD103+ DCs played a pathogenic role through activation of CD8+ T cells. Treatment with a Flt3 inhibitor specifically depleted CD103+ DCs and significantly reduced renal injury. The effect of Flt3 inhibition is currently being studied in anti-GBM disease and IRI.

Conclusion

Kidney CD103+ DC numbers correlate with severity of human kidney disease. In experimental kidney disease, CD103+ DCs play a pathogenic role through activation of CD8+ T cells. Targeting CD103+DCs with Flt3 inhibitors effectively reduces renal injury, suggesting a novel therapeutic strategy with accelerated translational potential through drug repurposing.