先前的研究发现，在通过Tregs治疗早期抗GBM疾病时，cDC1对其有保护作用，但在晚期阿霉素肾病中通过CD8 + T细胞具有致病性。Flt3配体是cDC1发育所必需的生长因子，目前已被用于癌症治疗。我们进行了这项研究，以澄清在抗GBM疾病的不同时间点中cDC1作用和机制的角色，并旨在利用Flt3抑制剂的药物再利用来针对cDC1作为治疗抗GBM疾病的方法。 我们发现在人体抗GBM疾病中，cDC1的数量显著增加，比cDC2的比例更高。CD8 + T细胞的数量也显著增加，并且它们的数量与cDC1数量相关。在 XCR1-DTR 小鼠中，在抗GBM疾病小鼠中晚期 (第12-21天)，而不是早期 (第3-12天) 的cDC1耗尽减轻了肾损伤。从抗GBM疾病小鼠的肾脏分离出的cDC1在晚期但不在早期阶段具有促炎症表型（即高水平表达IL-6和IL-12）。在耗尽的晚期模型中，CD8 + T细胞的数量也减少了，但不是Tregs。 从抗GBM疾病小鼠的肾脏分离出的CD8 + T细胞表达高水平的细胞毒素（颜粒酶B和穿孔素）和促炎症细胞因子（TNF-α和IFN-γ），在通过白喉毒素耗尽cDC1之后，它们的表达显着降低。在野生型小鼠中，使用Flt3抑制剂重复这些发现。因此，cDC1通过激活CD8 + T细胞在抗GBM疾病中具有致病性。通过耗尽cDC1，Flt3抑制成功减轻了肾损伤。再利用Flt3抑制剂具有成为抗GBM疾病的新型治疗策略的潜力。版权所有©2023。Elsevier Inc.出版。

Previous studies found cDC1s to be protective in early stage anti-GBM disease through Tregs, but pathogenic in late stage Adriamycin nephropathy through CD8+ T cells. Flt3 ligand is a growth factor essential for cDC1 development and Flt3 inhibitors are currently used for cancer treatment. We conducted this study to clarify the role and mechanisms of effects of cDC1s at different time points in anti-GBM disease. In addition, we aimed to utilize drug repurposing of Flt3 inhibitors to target cDC1s as a treatment of anti-GBM disease. We found that in human anti-GBM disease, the number of cDC1s increased significantly, proportionally more than cDC2s. The number of CD8+ T cells also increased significantly and their number correlated with cDC1 number. In XCR1-DTR mice, late (day 12-21) but not early (day 3-12) depletion of cDC1s attenuated kidney injury in mice with anti-GBM disease. cDC1s separated from kidneys of anti-GBM disease mice were found to have a pro-inflammatory phenotype (i.e. express high level of IL-6 and IL-12) in late but not early stage. In the late depletion model, the number of CD8+ T cells was also reduced, but not Tregs. CD8+ T cells separated from kidneys of anti-GBM disease mice expressed high levels of cytotoxic molecules (granzyme B and perforin) and inflammatory cytokines (TNF-α and IFN-γ), and their expression reduced significantly after cDC1 depletion with diphtheria toxin. These findings were reproduced using a Flt3 inhibitor in wild type mice. Therefore, cDC1s are pathogenic in anti-GBM disease through activation of CD8+ T cells. Flt3 inhibition successfully attenuated kidney injury through depletion of cDC1s. Repurposing Flt3 inhibitors has potential as a novel therapeutic strategy for anti-GBM disease.Copyright © 2023. Published by Elsevier Inc.