LP-086 Dexamethasone-incorporated immunomodulatory PDMAEMA-PLGA nanoparticles potentially induced tolerogenic dendritic cells and ameliorated lupus disease by mediating antigen-specific immune tolerance

BackgroundRecent advances in the treatment of systemic lupus erythematosus (SLE) have focused on inducing specific immune tolerance to avoid complications from the long-term use of immunosuppressive drugs. Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and immune tolerance. Since altered tolerogenicity of DCs contributes to the development and pathogenesis of SLE, DC-targeted therapies aimed at inducing self-tolerance have become of great importance for the treatment of SLE and autoimmune diseases. Our current study developed a new nanoparticle (NP) containing PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ.MethodsThe in vitro tolerogenic effects of PDMAEMA-PLGA NPs and dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) were tested in conventional DCs generated from murine bone marrow (BM-cDCs) using FLT3L and GM-CSF in comparison with pure dexamethasone. The uptake of PDMAEMA-PLGA NPs by DCs was investigated in vivo and the in vivo therapeutic efficacy of Dex-NPs was observed in Fcgr2b-/- lupus-prone mice.ResultsPDMAEMA-PLGA NPs provided sustained drug release profiles and exhibited immunosuppressive activity in BM-cDCs. PDMAEMA-PLGA NPs strengthened the dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from immunogenic to tolerogenic state, and BM-cDCs treated with Dex-NPs efficiently mediated Treg expansion in vitro. PDMAEMA-PLGA NPs were actively captured by DCs in vivo probably in a particle size-dependent manner. Furthermore, Dex-NPs potentially ameliorated lupus activity in Fcgr2b-/- mice by reducing renal inflammation, anti-double-strand DNA antibodies, serum IL-6, serum creatinine, and proteinuria. Dex-NP therapy markedly enhanced Foxp3+ Treg expansion in an antigen-specific manner in Fcgr2b-/- mice.ConclusionsThese findings substantiate the superior efficacy of our Dex-NPs and provide further support for clinical development as a potential therapy for SLE. Furthermore, Dex-NPs may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune diseases.