Affiliation:
1. Chinese Academy of Medical Sciences and Peking Union Medical College
Abstract
Abstract
Objectives
OX40 ligand (OX40L) locus genetic variants have relationships with the risk for systemic lupus erythematosus (SLE), OX40L blockade has been shown to ameliorate renal damage and suppress autoantibody production in NZB/W F1 mice. However, it is unclear how OX40L blockade delays lupus phenotype.
Methods
In present study, we examined the impact of blocking OX40L using anti-OX40L in the MRL/lpr murine model of lupus. Mice were sorted into 3 groups with 9 ~ 11 mice per group as follows: IgG treatment, Cyclophosphamide (CTX) treatment, and anti-OX40L treatment. Treated mice were harvested, and samples of serum, kidney, and spleen were collected for outcome evaluation. Next, we investigated the impact of anti-OX40L on immunosuppression in KLH-immunized C57BL/6J mice aged 8 weeks through the detection of serum immunoglobulins (Igs) and splenocyte flow cytometry. In vitro treatment of anti-OX40L in CD4+ T and CD19+ B cells were used for exploring the roles of OX40L in SLE pathogenesis.
Results
Anti-OX40L delayed disease progression in MRL/lpr mice, accompanied by decreased production of anti-dsDNA, proteinuria, and Ig deposition in kidney, as well as lower frequencies of Th1 and Tfh cells in the spleen. Compared to the IgG group, anti-OX40L was found to up-regulate polyclonal CD4+ T cell differentiation into Tregs in vitro. In KLH-immunized mice, decreased levels of Igs, and plasmablast cells were observed in anti-OX40L group. Blocking OX40/OX40L signaling also inhibited TLR7-mediated differentiation of antibody secreting cells (ASCs) and production of antibody through the up-regulation of SPI-B, IRF8, and PAX5, and down-regulation of Xbp-1 in B cells in vitro.
Conclusion
Together, these results propose OX40L as a promising therapeutic target for SLE.
Publisher
Research Square Platform LLC