Type 1 conventional dendritic cells in kidney disease

Dendritic cells (DCs) are central orchestrators of the immune system, which regulate both innate and adaptive immune responses. They can be broadly categorized into plasmacytoid DCs (pDCs) and conventional DCs (cDCs). cDC1s are a major subset of conventional DCs and play an important role in kidney disease. In this study, I firstly examined cDC1s in human kidney disease through analysing frozen human kidney biopsy samples. Secondly, I investigated the mechanisms of effects of cDC1s in experimental kidney disease, namely Adriamycin nephropathy and anti-GBM disease. Lastly, I explored the therapeutic potential of targeting cDC1s by repurposing Flt3 inhibitor for treatment of kidney disease. In the human study, I found that the number of cDC1s correlated with disease severity in acute tubular necrosis, number of crescents in pauci-immune glomerular nephritis, interstitial fibrosis in IgA nephropathy and lupus nephritis, as well as prognosis in IgA nephropathy. The number of CD8+ T cells also increased significantly in these conditions and cDC1 number correlated with CD8+ T cell number. These findings reflected a possible role of cDC1s in these conditions and their association with CD8+ T cells suggested a combined mechanism in keeping with the results in animal models. In the animal experiments, I studied cDC1s in vitro and in vivo using wild type as well as transgenic XCR1-DTR mice. In both Adriamycin nephropathy and anti-GBM disease, I found the number of cDC1s increased significantly. Depletion of cDC1s attenuated kidney injury, suggesting their pathogenic role. The mechanisms underlying cDC1 mediated kidney injury was demonstrated to relate to their superior ability to activate CD8+ T cells. Flt3 is a receptor tyrosine kinase which regulates the differentiation of DCs and a Flt3 inhibitor is currently being used in cancer treatment. I demonstrated that a Flt3 inhibitor can deplete cDC1s with relative specificity. The Flt3 inhibitor attenuated kidney injury in both Adriamycin nephropathy and anti-GBM disease. Therefore, repurposing Flt3 inhibitor could be a novel therapeutic strategy to treat kidney disease.