T CHEN1,2,3, Q CAO1,2, R WANG1,2, P RAO1,2, G ZHENG1,2, V LEE1,2,3, N ROGERS1,2,3, M PATEL1,3, CH P’NG1,3, H YU2, S ALEXANDER4, Y WANG1,2, D HARRIS1,2,3
1University of Sydney, Westmead, Australia, 2The Westmead Institute for Medical Research, Westmead, Australia, 3Westmead Hospital, Westmead, Australia, 4Children’s Hospital at Westmead, Westmead, Australia

Aim: 1- To examine CD141+ dendritic cells (DCs; human homologue of 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
Background: Whereas CD103+ 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.
Methods: A human study included 294 kidney biopsies from 01/07/2016 to 01/04/2017. For animal experiments, we used murine Adriamycin Nephropathy (AN), anti-GBM disease and ischaemia 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 fibrosis in IgA nephropathy (P=0.025), but not 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.
Conclusions: Kidney CD103+ DC numbers correlate with severity of human kidney disease. Targeting CD103+DCs with Flt3 inhibitors effectively reduces renal injury in experimental kidney disease, suggesting a novel therapeutic strategy with accelerated translational potential through drug repurposing.

Dr Titi Chen is a nephrology fellow and NHMRC postgraduate scholar. She has a passion for research and is currently completing her PhD through the University of Sydney.


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