TARGETING CD103+ DENDRITIC CELLS USING FLT3 INHIBITORS FOR TREATMENT OF KIDNEY DISEASE; RELEVANCE TO HUMAN KIDNEY DISEASE.

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.


Biography:
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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The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

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