Bone marrow derived dendritic cells modified by lentiviral-mediated RelB shRNA possess tolerogenic phenotype and functions on lupus splenic lymphocytes

Abstract

Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and remains challenging in treatment.Dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis. DCs that can induce tolerogenicity appear aspotential cell-based therapy in this condition. In this study, we examined the in vitro tolerogenic properties of bone-marrow derived DCs (BMDCs) in themurine lupus setting.

Methods: We used lentiviral transduction of RelB-silencing shRNA to modify expression of RelB, a key transcription factor regulating DC maturation, in BMDCs fromMRL/MpJ mice. Tolerogenic properties of RelB-modified DCs were compared to scrambled control (SC)-modified DCs.

Results: RelB expression was found to be significantly reduced in RelB-modified DCs derived from MRL/MpJ mice, wild type of the same genetic background asMRL/lpr lupus-prone mice. These MRL/MpJ RelB-modified DCs displayed semi-mature phenotype with expression of lower levels of co-stimulatorymolecules compared to SC-modified DCs. RelB-modified DCs were found to be low producer of IL-12p70, can induce hyporesponsiveness of splenic Tcells from MRL/MpJ and lupus-prone MRL/lpr mice. Furthermore, they downregulated IFN-γ expression and induced IL-10 producing T cells in MRL/MpJsplenocytes, and attenuated IFN-γ and IL-17 expression in MRL/lpr splenic CD4+ lymphocytes. Splenocytes primed by RelB-modified DCs demonstratedantigen-specific suppressive effect on allogeneic splenocytes.

Conclusion: RelB-silencing in DCs generates DCs of tolerogenic properties with immunomodulatory function and appears as potential option of cell-targeted therapy.