α2-Macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism

被引:19
作者
Anderson, Ryan B. [1 ]
Cianciolo, George J. [1 ]
Kennedy, Margaret N. [1 ]
Pizzo, Salvatore V. [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
关键词
vaccine adjuvant; TLR9; dendritic cells; LRP;
D O I
10.1189/jlb.0407236
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 M-2) binds numerous biologically active macromolecules, including cytokines, chemokines, and growth factors, and can modulate their activity. Molecules bound to alpha M-2 are protected from interactions with neighboring macro-molecules and are targeted for receptor-mediated uptake by immune-competent cells. Here, we report that activated alpha M-2 (alpha M-2*) binds CpG ODN and enhances their immunostimulatory properties significantly. Murine macrophages treated with alpha M-2*-ODN complexes respond more rapidly and produce a greater cytokine response than induced by free CpG ODN. Using human PBMC, alpha M-2*-ODN complexes exhibit fourfold enhanced potency and 15-fold greater efficacy for stimulating production of inflammatory cytokines. alpha M-2* 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 M-2* 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.
引用
收藏
页码:381 / 392
页数:12
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