Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0407236 on October 29, 2007

Published online before print October 29, 2007
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(Journal of Leukocyte Biology. 2008;83:381-392.)
© 2008 by Society for Leukocyte Biology

{alpha}2-Macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism

Ryan B. Anderson, George J. Cianciolo, Margaret N. Kennedy and Salvatore V. Pizzo1

Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

1 Correspondence: Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710, USA. E-mail: pizzo001{at}mc.duke.edu

CpG oligodeoxynucleotides (ODN) stimulate the immune system and are under evaluation as treatments and vaccine adjuvants for infectious diseases, cancer, and immune system disorders. Although they have shown promising results in numerous clinical trials, the ultimate use of CpG ODN-based therapeutics may hinge on improved pharmacokinetics and reduced systemic side-effects. CpG ODN efficacy and potency might be enhanced greatly by packaging them into particles that protect them from degradation and specifically target them for uptake by immune-competent cells. The plasma proteinase inhibitor {alpha}2-macroglobulin ({alpha}2M) binds numerous biologically active macromolecules, including cytokines, chemokines, and growth factors, and can modulate their activity. Molecules bound to {alpha}2M are protected from interactions with neighboring macromolecules and are targeted for receptor-mediated uptake by immune-competent cells. Here, we report that activated {alpha}2M ({alpha}2M*) binds CpG ODN and enhances their immunostimulatory properties significantly. Murine macrophages treated with {alpha}2M*-ODN complexes respond more rapidly and produce a greater cytokine response than induced by free CpG ODN. Using human PBMC, {alpha}2M*-ODN complexes exhibit fourfold enhanced potency and 15-fold greater efficacy for stimulating production of inflammatory cytokines. {alpha}2M* targets delivery of CpG ODN specifically to immune-competent cells, which endocytose the complexes sixfold more rapidly than free CpG ODN. CpG ODN bound to {alpha}2M* are also protected from degradation by nucleases. This novel targeting technology may improve CpG ODN-based therapeutics by increasing efficacy at reduced doses, thus reducing side-effects and cost.

Key Words: vaccine adjuvant • TLR9 • dendritic cells • LRP






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