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LP-086 Dexamethasone-incorporated immunomodulatory PDMAEMA-PLGA nanoparticles potentially induced tolerogenic dendritic cells and ameliorated lupus disease by mediating antigen-specific immune tolerance
  1. Phuriwat Khiewkamrop1,2,3,
  2. Chonnavee Manipuntee2,4,
  3. Chamraj Kaewraemruaen5,
  4. Numpon Insin4,
  5. Asada Leelahavanichkul6,
  6. Nattiya Hirankarn3,7 and
  7. Patcharee Ritprajak2,8
  1. 1Graduate School, Chulalongkorn University, Bangkok, Graduate Program in Medical Microbiology, Thailand
  2. 2Research Unit in Integrative Immuno-Microbial Biochemistry and Bioresponsive Nanomaterials, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
  3. 3Center of Excellence in Immunology and Immune-Mediated Diseases, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  4. 4Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
  5. 5Department of Microbiology, Faculty of Liberal Arts and Science, Kasetsart University, Kamphaeng Saen Campus, Nakhon Pathom, Thailand
  6. 6Department of Microbiology, Translational Research in Inflammation and Immunology Research Unit (TRIRU), Bangkok, Thailand
  7. 7Department of Microbiology, Immunology Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  8. 8Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand


Background Recent 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.

Methods The 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.

Results PDMAEMA-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.

Conclusions These 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.

  • Systemic lupus erythematosus
  • Tolerogenic dendritic cells
  • PDMAEMA-PLGA nanoparticle

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