CpG penta- and hexadeoxyribonucleotides as potent immunomodulatory agents.
We demonstrate a new design for immunomodulatory CpG DNA containing two sequences each with as few as five or six-nucleotides joined together via 3(')-3(') linkers. These do not require the -PuPu(Py)CGPyPy- hexameric motif generally found essential for CpG DNA immune stimulation. These novel, short-immunomers show potent immunostimulatory activity manifested by IL-12 and IL-6 secretion in murine spleen cell and PBMC cultures and splenomegaly in vivo. Short-immunomers show strong activation of NF-kappaB and stress-activated signaling pathways and induce cytokines in J774 cell cultures. The same sequences also induce cytokines in healthy human PBMC cultures whereas conventional CpG DNA requires different optimal sequences for murine and human immune cells. Additionally, short-immunomers inhibit IL-5 secretion and induce IFN-gamma secretion in conalbumin-sensitized mouse spleen cell cultures, suggesting reversal of established Th2 responses to Th1 type responses. Short-immunomer also inhibits growth of MCF-7 human tumor xenograft in nude mice. This is the first report of activity with such short DNA sequences and also of sequences lacking hexameric motifs proposed in earlier studies.
Bhagat
Lakshmi
L
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, USA.
Zhu
Fu Gang
FG
Yu
Dong
D
Tang
Jimmy
J
Wang
Hui
H
Kandimalla
Ekambar R
ER
Zhang
Ruiwen
R
Agrawal
Sudhir
S
D000276:Adjuvants, Immunologic; D000818:Animals; D002478:Cells, Cultured; D015226:Dinucleoside Phosphates / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000276:Adjuvants, Immunologic; D015226:Dinucleoside Phosphates; D007371:Interferon-gamma; D018664:Interleukin-12; D015848:Interleukin-5; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D048051:p38 Mitogen-Activated Protein Kinases; C015772:CpG dinucleotide