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* Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilian University of Munich, Munich, Germany; and
Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilian University of Munich, Munich, Germany
Viral nucleic acids are recognized by specific pattern-recognition receptors of the Toll-like and RIG-I-like receptor families. Synthetic DNA and RNA oligonucleotides can activate the immune system through these receptors and potentiate Ab and CD8 cytotoxic responses to Ags. Systemic application of immunostimulatory oligonucleotides however also results in a generalized, non-Ag-specific stimulation of the immune system. In this study, we have dissociated the induction of an Ag-specific response from the systemic immune activation generally associated with immunostimulatory oligonucleotides. Delivery of CpG oligodeoxynucleotides that bind TLR9 by cationized gelatin-based nanoparticles potentiates the in vivo generation of an Ag-specific cytotoxic T cell and Ab response. Furthermore, immunization with CpG-loaded nanoparticles induces a protective antitumoral response in a murine model of melanoma. The systemic release of proinflammatory cytokines and widespread immunostimulation associated with free CpG is however completely abolished. In addition, we show that gelatin nanoparticle formulation prevents the destruction of lymphoid follicles mediated by CpG. Nanoparticle-delivered CpG, in contrast to free CpG, are selectively targeted to APCs in the lymph nodes where they mediate local immune stimulation. We describe a novel strategy to target immunostimulatory oligonucleotides to the initiation site of the immune response while at the same time protecting from an indiscriminate and generalized activation of the immune system.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from the Else-Kröner Fresenius Foundation (to C.B. and S.E.), the Deutsche Krebshilfe (10-2214-En3) (to S.E.), the German Research Foundation (DFG En 169/7-2 and Graduiertenkolleg 1202 to C.B. and SFB-TR 36 to S.E.) and from LMUexcellent (cluster CiPSM 114 and research professorship to S.E.).
2 C.B. and D.A. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Carole Bourquin, Division of Clinical Pharmacology, Ziemssenstraβe 1, 80336 München, Germany. E-mail address: carole.bourquin{at}med.uni-muenchen.de
4 Abbreviations used in this paper: NP, nanoparticle; DC, dendritic cell; Treg, regulatory T cell.
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