Hierarchical recognition of CpG motifs expressed by immunostimulatory oligodeoxynucleotides.
Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs trigger human PBMC to proliferate and secrete Ig, cytokines and chemokines. CpG ODN have entered clinical trials, and show promise as vaccine adjuvants, antiallergens, and for the treatment of infectious diseases and cancer. ODNs under consideration for human use vary in the sequence, number and location of the CpG motifs they contain. Yet little is known of the magnitude of the immune response elicited by these diverse ODNs, or the rules governing their interaction with immune cells. This work compares the proliferative, IgM, IL-6 and IP-10 response of PBMC from normal donors to a diverse panel of CpG ODNs. Results indicate that ODNs expressing 3-4 different CpG motifs are strongly stimulatory. The location of these motifs is important, with those at the 5' end exerting the greatest influence on ODN activity. These findings provide a basis for the rational design of ODNs optimized for clinical use.
Klinman
D M
DM
Section of Retroviral Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda 20892, USA. Klinman@cber.fda.gov
Currie
D
D
D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D018899:CpG Islands / Q000276:immunology*; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D007075:Immunoglobulin M; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides