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Lookup NU author(s): Dr Lei HuangORCiD, Dr Henrique De Paula LemosORCiD, Emeritus Professor Andrew MellorORCiD
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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.
Author(s): Huang L, Lemos H, Li L, Li M, Chandler PR, Baban B, McGaha TL, Ravishankar B, Lee J, Munn DH, Mellor AL
Publication type: Article
Publication status: Published
Journal: The Journal of Immunology
Year: 2012
Volume: 188
Issue: 10
Pages: 4913-4920
Print publication date: 15/05/2012
ISSN (print): 0022-1767
ISSN (electronic): 1550-6606
Publisher: American Association of Immunologists
URL: http://doi.org/10.4049/jimmunol.1103668
DOI: 10.4049/jimmunol.1103668
PubMed id: 22516958
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