title: PLGA nanoparticles enhance the expression of retinaldehyde dehydrogenase enzymes in dendritic cells and induce FoxP3(+) T-cells in vitro.
abstract: Many autoimmune diseases and other chronic inflammatory disorders are characterized by defective FoxP3(+) regulatory T-cell (Treg) mediated suppression. A potential treatment option for these disorders is to increase the number and activity of Tregs locally. Both PLGA (poly-lactic-co-glycolic acid) and TMC-TPP (N-trimethyl chitosan tripolyphosphate) nanoparticles (NP) have been described to enhance T cell activation upon nasal application. Since, PLGA NP and TMC-TPP NP differentially affect CD4(+) T-cell differentiation, we investigated in vitro the capacity of both delivery systems to trigger retinoic acid (RA) production in dendritic cells (DCs) as a strategy to enhance the induction of FoxP3(+) T-cells. We generated ovalbumin (OVA)-encapsulated PLGA NP and TMC-TPP NP that were similar in size (400nm) but differed in their surface charge and other physico-chemical properties. We demonstrate that OVA-specific T-cells that are activated by cervical lymph node (CLN)-derived DCs treated with PLGA NP or TMC-TPP NP show more FoxP3 expression than T-cells that are activated by inguinal lymph node (ILN) cells. We demonstrate that only OVA-encapsulated PLGA NP enhance the induction of FoxP3 in activated T-cells via a TGF-β and RA dependent mechanism by enhancing retinaldehyde dehydrogenase enzyme (RALDH) expression in CLN-derived DCs that is required for RA production. Additionally, detailed analysis of the CD4(+) T-cell response reveals that PLGA NP induce both IL-10 and IFN-γ production, while TMC-TPP NP induce mainly Th17 production. Underlining that both APC origin and NP characteristics determine the expression level of FoxP3 in activated T-cells. In conclusion, our data suggest that PLGA NP enhance the induction of FoxP3(+) T-cells in the CLN through modulation of DC function and we suggest that they might be a suitable nasal delivery system to treat a wide variety of autoimmune diseases and other chronic inflammatory disorders.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Keijzer
authors.forename: Rachel
authors.initials: R
authors.lastname: Spiering
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Silva
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
authors.forename: Lonneke
authors.initials: L
authors.lastname: Vervelde
authors.forename: Femke
authors.initials: F
authors.lastname: Broere
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology*; D019344:Lactic Acid / Q000008:administration & dosage*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage*; D010047:Ovalbumin / Q000276:immunology; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050697:Retinal Dehydrogenase / Q000276:immunology*
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase