title: Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells.
abstract: Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-αβ) and II (IFN-γ), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-γ receptor signaling was not essential for this response. Moreover, systemic IFN-γ release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-αβ release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-αβ production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-γ. DNP treatment to induce IDO and activate Tregs blocked Ag-specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune-mediated destruction in clinical hyperimmune syndromes.
authors.affiliation: Immunotherapy Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Henrique P
authors.initials: HP
authors.lastname: Lemos
authors.forename: Lingqian
authors.initials: L
authors.lastname: Li
authors.forename: MingHui
authors.initials: M
authors.lastname: Li
authors.forename: Phillip R
authors.initials: PR
authors.lastname: Chandler
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.forename: Buvana
authors.initials: B
authors.lastname: Ravishankar
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Lee
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D004269:DNA, Bacterial / Q000235:genetics* / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005818:Genetic Engineering / Q000379:methods; D007155:Immunologic Factors / Q000627:therapeutic use*; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000627:therapeutic use*; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011089:Polydeoxyribonucleotides; D011094:Polyethyleneimine