35:
163:). The five classes are Class A (Type D), Class B (Type K), Class C, and Class P. It is important to note that during the discovery process, the "Classes" were not defined until much later when it became evident that ODN with certain characteristics elicited specific responses. Because of this, most ODN referred to in the literature use numbers (i.e., ODN 2006, ODN 2007, ODN 2216, ODN D35, ODN K3, etc.). The numbers are arbitrary and come from testing large numbers of ODN with slight variations in attempts to find the optimal sequence. In addition, some papers will give different names to previously described ODN, complicating the naming convention even more.
125:, but it was not until 1983 that Tokunaga et al. specifically identified bacterial DNA as the underlying component of the lysate that elicited the response. Then, in 1995 Krieg et al. demonstrated that the CpG motif within bacterial DNA was responsible for the immunostimulatory effects and developed synthetic CpG ODN. Since then, synthetic CpG ODN have been the focus of intense research due to the Type I pro-
210:
Class A ODN typically contain 7 to 10 PS-modified bases at one or both ends that resist degradation by nucleases and increase the longevity of the ODN. The above rules strictly define the class, but variability of the sequence within these "rules" is possible. It should also be noted that changes to
158:
with variations in the number and location of CpG dimers, as well as the precise base sequences flanking the CpG dimers. This led to the creation of five unofficial classes or categories of CpG ODN based on their sequence, secondary structures, and effect on human peripheral blood mononuclear cells
153:
in the body and poly G tail enhances cellular uptake. The poly G tails form intermolecular tetrads that result in high molecular weight aggregates. These aggregates are responsible for the increased activity the poly G sequence impart; not the sequence itself. Numerous sequences have been shown to
219:
CG Py Py-3', was found to be the most active when compared to several other sequences. The poly G tail found at either end of the DNA strand can vary in length and even number (Type D only have a poly G sequence on the 3'end), but its presence is critical to the activity of the molecule.
439:
Tokunaga T, Yamamoto H, Shimada S, Abe H, Fukuda T, Fujisawa Y, Furutani Y, Yano O, Kataoka T, Sudo T (April 1984). "Antitumor activity of deoxyribonucleic acid fraction from
Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity".
228:
Krieg et al. was the first to describe Class B ODN in 1995. Class B ODN (i.e. ODN 2007) are strong stimulators of human B cell and monocyte maturation. They also stimulate the maturation of pDC but to a lesser extent than Class A ODN and very small amounts of IFNα.
171:
One of the first Class A ODN, ODN 2216, was described in 2001 by Krug et al. This class of ODN was distinctly different from the previously described Class B ODN (i.e., ODN 2006) in that it stimulated the production of large amounts of
248:
The strongest ODN in this class have three 6mer sequences. B ODN have been studied extensively as therapeutic agents because of their ability to induce a strong humoral immune response, making them ideal as a
211:
the sequence will affect the magnitude of the response. For example, the internal palindrome sequence can be 4 to 8 base pairs in length and vary in the order of bases, however the pattern, 5'-
531:"Phosphodiester CpG oligonucleotides as adjuvants: polyguanosine runs enhance cellular uptake and improve immunostimulative activity of phosphodiester CpG oligonucleotides in vitro and in vivo"
478:
Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (April 1995). "CpG motifs in bacterial DNA trigger direct B-cell activation".
145:(PS) backbone instead of the typical phosphodiester backbone and a poly G tail at the 3' end, 5' end, or both. PS modification protects the ODN from being degraded by
695:
Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis HL, Krieg AM (February 2000).
93:) due to their abundance in microbial genomes but their rarity in vertebrate genomes. The CpG PAMP is recognized by the pattern recognition receptor (
408:
Coley WB (January 1991). "The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893".
349:
176:, the most important one being IFNα, and induced the maturation of plasmacytoid dendritic cells. Class A ODN are also strong activators of
275:"Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization"
672:
655:
697:"Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo"
94:
656:"Identification of CpG oligonucleotide sequences with high induction of IFN-alpha/beta in plasmacytoid dendritic cells"
654:
Krug A, Rothenfusser S, Hornung V, Jahrsdörfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G (July 2001).
742:
121:, a mixture of bacterial cell lysate, has immunostimulatory properties that could reduce the progression of some
619:
Vollmer J, Krieg AM (March 2009). "Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists".
373:
Rothenfusser S, Tuma E, Endres S, Hartmann G (December 2002). "Plasmacytoid dendritic cells: the key to CpG".
747:
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118:
106:
86:
66:
58:
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141:
Synthetic CpG ODN differ from microbial DNA in that they have a partially or completely
17:
555:
530:
78:
70:
386:
736:
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417:
309:
274:
142:
74:
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126:
336:. Current Topics in Microbiology and Immunology. Vol. 270. pp. 145–54.
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696:
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82:
632:
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Proceedings of the
National Academy of Sciences of the United States of America
580:"Necessity of oligonucleotide aggregation for toll-like receptor 9 activation"
216:
197:
34:
299:
453:
146:
122:
722:
681:
640:
605:
596:
579:
564:
394:
359:
38:
The different classes of ODN elicit different responses in pDC and B cells.
507:
461:
425:
318:
253:
181:
54:
28:
73:
link between consecutive nucleotides, although some ODN have a modified
673:
10.1002/1521-4141(200107)31:7<2154::AID-IMMU2154>3.0.CO;2-U
273:
Weiner GJ, Liu HM, Wooldridge JE, Dahle CE, Krieg AM (September 1997).
250:
102:
62:
499:
212:
193:
The presences of a poly G sequence at the 5' end, the 3' end, or both
89:. CpG motifs are considered pathogen-associated molecular patterns (
150:
90:
33:
160:
98:
50:
332:
Bauer S, Wagner H (2002). "Bacterial CpG-DNA licenses TLR9".
203:
GC dinucleotides contained within the internal palindrome
129:
response they elicit and their successful use as vaccine
529:
Dalpke AH, Zimmermann S, Albrecht I, Heeg K (May 2002).
578:
Wu CC, Lee J, Raz E, Corr M, Carson DA (August 2004).
334:
Toll-Like
Receptor Family Members and Their Ligands
241:A fully phosphorothioated (PS-modified) backbone
238:One or more 6mer CpG motif 5'-Pu Py C G Py Pu-3'
473:
471:
101:), which is constitutively expressed only in
8:
109:(pDCs) in humans and other higher primates.
410:Clinical Orthopaedics and Related Research
712:
671:
595:
554:
308:
298:
233:Structural features defining Class B ODN:
188:Structural features defining Class A ODN:
442:Journal of the National Cancer Institute
244:Generally 18 to 28 nucleotides in length
117:Since 1893, it has been recognized that
265:
77:(PS) backbone instead. When these CpG
49:) are short single-stranded synthetic
7:
584:The Journal of Biological Chemistry
25:
547:10.1046/j.1365-2567.2002.01410.x
418:10.1097/00003086-199101000-00002
206:A partially PS-modified backbone
660:European Journal of Immunology
621:Advanced Drug Delivery Reviews
1:
387:10.1016/S0198-8859(02)00749-8
69:("G"). The "p" refers to the
714:10.4049/jimmunol.164.3.1617
342:10.1007/978-3-642-59430-4_9
764:
633:10.1016/j.addr.2008.12.008
26:
53:molecules that contain a
43:CpG oligodeoxynucleotides
300:10.1073/pnas.94.20.10833
97:) Toll-Like Receptor 9 (
27:Not to be confused with
18:CpG Oligodeoxynucleotide
597:10.1074/jbc.M311662200
39:
701:Journal of Immunology
454:10.1093/jnci/72.4.955
37:
61:("C") followed by a
492:1995Natur.374..546K
291:1997PNAS...9410833W
137:Structural features
174:Type I interferons
40:
351:978-3-642-63975-3
180:through indirect
143:phosphorothioated
105:and plasmacytoid
16:(Redirected from
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743:Immunostimulants
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375:Human Immunology
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87:immunostimulants
75:phosphorothioate
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618:
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590:(32): 33071–8.
577:
576:
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486:(6522): 546–9.
477:
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469:
438:
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433:
407:
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331:
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285:(20): 10833–7.
272:
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169:
139:
115:
107:dendritic cells
67:deoxynucleotide
59:deoxynucleotide
32:
23:
22:
15:
12:
11:
5:
761:
759:
751:
750:
745:
735:
734:
729:
728:
707:(3): 1617–24.
687:
666:(7): 2154–63.
646:
627:(3): 195–204.
611:
570:
521:
467:
431:
400:
381:(12): 1111–9.
365:
350:
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246:
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208:
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156:stimulate TLR9
138:
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114:
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85:, they act as
71:phosphodiester
24:
14:
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10:
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6:
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2:
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748:Immune system
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541:(1): 102–12.
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459:
455:
451:
448:(4): 955–62.
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443:
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419:
415:
412:(262): 3–11.
411:
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119:Coley's toxin
112:
110:
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96:
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88:
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76:
72:
68:
65:triphosphate
64:
60:
57:triphosphate
56:
52:
48:
44:
36:
30:
19:
704:
700:
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196:An internal
187:
186:
170:
140:
127:inflammatory
116:
83:unmethylated
46:
42:
41:
184:signaling.
737:Categories
535:Immunology
260:References
198:palindrome
123:carcinomas
215:Pu CG Pu
147:nucleases
131:adjuvants
723:10640783
682:11449369
641:19211030
606:15184382
565:11972638
395:12480254
360:12467249
254:adjuvant
200:sequence
182:cytokine
178:NK cells
149:such as
55:cytosine
29:CpG site
556:1782689
516:4261304
508:7700380
488:Bibcode
462:6200641
426:1984929
319:9380720
287:Bibcode
251:vaccine
224:Class B
167:Class A
113:History
103:B cells
63:guanine
47:CpG ODN
721:
680:
639:
604:
563:
553:
514:
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480:Nature
460:
424:
393:
358:
348:
317:
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79:motifs
512:S2CID
310:23500
161:PBMCs
151:DNase
91:PAMPs
719:PMID
678:PMID
637:PMID
602:PMID
561:PMID
504:PMID
458:PMID
422:PMID
391:PMID
356:PMID
346:ISBN
315:PMID
99:TLR9
81:are
45:(or
709:doi
705:164
668:doi
629:doi
592:doi
588:279
551:PMC
543:doi
539:106
496:doi
484:374
450:doi
414:doi
383:doi
338:doi
305:PMC
295:doi
95:PRR
51:DNA
739::
717:.
703:.
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676:.
664:31
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635:.
625:61
623:.
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510:.
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470:^
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389:.
379:63
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344:.
313:.
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283:94
281:.
277:.
256:.
217:Py
213:Pu
133:.
725:.
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684:.
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567:.
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159:(
31:.
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