Journal of Leukocyte Biology
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A more recent version of this article appeared on February 1, 2008

Published online before print October 29, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407236

Received for publication April 20, 2007.
Revised August 6, 2007.
Accepted for publication August 30, 2007.

Article

{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. Pizzo @

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

@ To whom correspondence should be addressed. E-mail: Pizzo001{at}mc.duke.edu.


  Abstract

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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Copyright © 2007 by the Society for Leukocyte Biology.