Immunosuppressive Polymeric Nanoparticles Targeting Dendritic Cells Alleviate Lupus Disease in Fcgr2b-/- Mice by Mediating Antigen-Specific Immune Tolerance

Abstract

Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and tolerance. Hyperresponsiveness and altered tolerogenicity of DCs contribute to the development and pathogenesis of system lupus erythematosus (SLE); therefore, DC-targeted therapies aimed at inducing specific immune tolerance have become of great importance for the treatment of SLE. This study developed a new nanoparticle (NP) containing a biodegradable PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ. PDMAEMA-PLGA NPs provided sustained drug release and exhibited immunosuppressive activity in FLT3L and GM-CSF-derived bone marrow in conventional DCs (BM-cDCs). PDMAEMA-PLGA NPs improved dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from an immunogenic to tolerogenic state, and BM-cDCs treated with dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) efficiently mediated regulatory T cell (Treg) expansion in vitro. Dex-NP therapy potentially alleviated lupus disease in Fcgr2b-/- mice by mediating Foxp3+ Treg expansion in an antigen-specific manner. Our findings substantiate the superior efficacy of DC-targeted therapy using the PDMAEMA-PLGA NP delivery system and provide further support for clinical development as a potential therapy for SLE. Furthermore, PDMAEMA-PLGA NP may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune disease, allergy, and transplant rejection.

Polymeric Particle BAM15 Targeting Macrophages Attenuates the Severity of LPS-Induced Sepsis: A Proof of Concept for Specific Immune Cell-Targeted Therapy

“…PLGA particles were synthesized using a single emulsion/solvent evaporation [ 19 , 20 ]. Briefly, 50:50 lactide:glycolide PLGA (Sigma-Aldrich) (100 mg) in dichloromethane (10 mL) (RCI Labscan, Bangkok, Thailand) was homogenized for 2 min before the organic solvent was evaporated at 25 °C with magnetic stirring (2 h).…”

“…Additionally, PLGA particles can destabilize endosomes, induce endosomal escape, and deliver cargo to specific target cells [ 17 , 18 ]. We previously developed PLGA-based particles for drug delivery to dendritic cells (DCs) [ 19 , 20 ], while the delivery to macrophages in a similar aspect is also interesting. Therefore, BAM15-loaded PLGA may be an interesting anti-inflammatory drug for the treatment of several pro-inflammatory conditions.…”

Regulatory dendritic cell therapy in organ transplantation

“…Loss of Bat3 redirects acetyl coenzyme A to increase cell intrinsic steroidogenesis [6 ▪▪ ]. The enhanced steroidogenesis in Bat3-deficient dendritic cell suppresses T-cell responses, suggesting a more complicated relationship between dendritic cell signalling and known checkpoint inhibitors [6 ▪▪ ,45 ▪ ]. Nonetheless, following the completion of current clinical trials, such work may prove fundamental to the field, akin to the impact of c himeric a ntigen r eceptor (CAR) T-cells, where the use of various chimeric immunoreceptors/antigens to direct cell specific immunologic functions has achieved significant success.…”

“…For example, Elsayed et al [51 ▪ ] isolated and used human-derived DCreg exosomes in vitro to downregulate costimulatory molecules and induced upregulation of PD-L1 on recipient dendritic cells, which further induced Tregs [48]. Approaches applied in autoimmunity and allergy/hypersensitivity, such as the administration of DC-targeting, dexamethasone-incorporating nanoparticles for lupus, or exposure of monocytes to allergoid-mannan conjugates for allergies, alter dendritic cell towards a tolerogenic state [45 ▪ ,49 ▪ ]. In a murine heart transplant model, the bioactive metabolite monomethyl fumarate (MMF), significantly reduces acute rejection and prolongs allograft survival by inducing tolerogenic dendritic cells [50 ▪ ].…”