Tolerogenic dendritic cells immunotherapy protects against IgA nephropathy.

Abstract

This study aimed to investigate the therapeutic efficacy of tolerogenic dendritic cells (tolDCs) in IgA nephropathy (IgAN) mice. Male C57BL/6 mice were used to construct an IgAN model via oral mucosal immunization, while tolDCs were generated by exposing bone marrow-derived dendritic cells (BMDCs) to IL-10 and characterized for their immunosuppressive phenotype and function; wild-type (WT) and IgAN mice then received either PBS or tolDCs treatments, followed by comprehensive assessments of renal functional parameters, histopathological changes, and inflammatory cytokines profiles. The IgAN mouse model was successfully established by week 8 post-immunization, exhibiting characteristic renal pathology including glomerular mesangial IgA deposition, accompanied by mesangial cells hyperplasia and mesangial matrix expansion. IL-10-induced tolDCs exhibited a stable immunosuppressive phenotype: Compared with BMDCs, tolDCs exhibited a 3.5-fold up-regulation in PD-L1 surface expression and a 7.7-fold increase in IL-10 protein level, while IL-12 protein expression remained unchanged. Functionally, tolDCs demonstrated targeted migration to the kidneys and promoted regulatory T cells (Tregs) differentiation in IgAN mice. Therapeutic administration of tolDCs significantly attenuated disease progression: compared with the IgAN-PBS group, the IgAN-tolDCs group showed 59.3% and 55.4% reductions in glomerular and tubulointerstitial IgA deposition, respectively, accompanied by 5.5-fold and 2.9-fold increases in Tregs infiltration. At the inflammatory cytokines level, the mRNA and protein expression of renal IL-10 was up-regulated, while renal IL-12 and TGF-β was down-regulated in the IgAN-tolDCs group. Renal function parameters remained stable in the IgAN-tolDCs group, confirming the safety of tolDCs immunotherapy. In conclusion, IL-10-induced tolDCs exhibit a stable immunosuppressive phenotype and can migrate to the kidneys of IgAN mice, and their therapeutic administration alleviates renal IgA deposition, promotes renal Treg accumulation, and suppresses pro-inflammatory cytokine expression, collectively attenuating renal immunoinflammatory injury, supporting tolDCs as a promising targeted therapy for IgAN.