Polymeric Nanoparticles Containing Both Antigen and Vitamin D₃ Induce Antigen-Specific Immune Suppression

Abstract

The active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 (aVD 3 ), is known to exert beneficial effects in the treatment of autoimmune diseases because of its immunosuppressive effects. However, clinical application of aVD 3 remains limited because of the potential side effects, particularly hypercalcemia. Encapsulation of aVD 3 within biodegradable nanoparticles (NPs) would enhance the delivery of aVD 3 to antigen presenting cells, while preventing the potential systemic side effects of aVD 3 . In the present study, polymeric NPs containing ovalbumin (OVA) and aVD 3 (NP[OVA+aVD 3 ]) were prepared via the water-in-oil-in-water double emulsion solvent evaporation method, after which their immunomodulatory effects were examined. Bone marrow-derived immature dendritic cells (DCs) treated with NP(OVA+aVD 3 ) did not mature into immunogenic DCs but were converted into tolerogenic DCs, which express low levels of co-stimulatory molecules and MHC class II molecules, produce lower levels of pro-inflammatory cytokines while increasing the production of IL-10 and TGF-β, and induce the generation of Tregs. Intravenous injection with NP(OVA+aVD 3 ) markedly suppressed the generation of OVA-specific CTLs in mice. Furthermore, OVA-specific immune tolerance was induced in mice orally administered with NP(OVA+aVD 3 ). These results show that biodegradable NPs encapsulating both antigen and aVD 3 can effectively induce antigen-specific immune suppression.

Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance

“…Most importantly, VD3-raised DCs show tolerogenic stability in face of repeated rechallenge with pro-inflammatory stimuli, making VD3 a robust DC-tolerizing candidate in an already inflamed environment ( 163 ). In line with that, several recent studies in mice demonstrated that nanoparticles loaded with VD3 and OVA induced tolerogenic DCs with in vitro and in vivo suppressive capacity of OVA-specific T cells ( 164 , 165 ). Additionally, subcutaneous injection of VD3-loaded particles resulted in effective targeting of PD-L1 high draining lymph node DCs, resulting in amelioration of a RA disease model ( 165 ).…”

Engineering precision nanoparticles for drug delivery

“…Cellular targets for immune suppression include APCs 261 , autoreactive T cells and B cells 262 , and regulatory T cells and B cells 263 , 264 . Antigen-specific immunotherapy aims to reprogramme or reduce reactive cells or impart them with tolerance to certain antigens 260 .…”

“…NPs that deliver IL-2 and TGFβ can expand the number of regulatory T cells in vivo, suppressing the symptoms of lupus 263 . The active form of vitamin D 3 has immunosuppressive effects because it modulates dendritic cell function 261 . Active vitamin D 3 can cause hypercalcaemia when administered systemically, so NP delivery is a promising alternate strategy.…”

Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance

“…In previous reports, to improve the antigen-specific immune tolerance, autoantigen-encapsulated/conjugated nano/microparticles were additionally loaded with various immunosuppressive molecules including aryl hydrocarbon receptor 13 , 51 , 52 , anti - inflammatory cytokines 53 – 55 , immunosuppressive ligands and gene 56 – 58 , autoantigen - loaded MHC 56 , or immunosuppressive small molecules such as rapamycin 15 , 16 and vitamin D3 59 . These agents direct DCs and T cells in various immunological pathways to establish immune tolerance 60 .…”