Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo

Hartmann, Gunther; Weeratna, Risini D.; Ballas, Zuhair K.; Payette, Paul; Blackwell, Sue; Suparto, Irma Herawati; Rasmussen, Wendy; Waldschmidt, Marianella; Sajuthi, Dondin; Purcell, Robert H.; Davis, Heather L.; Krieg, Arthur Μ.

doi:10.4049/jimmunol.164.3.1617

Cited by 540 publications

(415 citation statements)

References 43 publications

(29 reference statements)

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“…In contrast, in the present study, we observed a high penetrance of arthritis in this rat strain using a similar protocol for injection of CpG/ IFA. The discrepancy of these results with the data of Ronaghy et al might be explained by the use of different oligodinucleotide sequences, since it has previously been shown that the immunostimulatory effect of CpG ODN is determined not only by the CpG motif itself, but also by the flanking nucleotide sequences (23).…”

Section: Discussionmentioning

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Oligodeoxynucleotides containing CpG motifs can induce T cell–dependent arthritis in rats

Svelander¹,

Harris²,

Lorentzen³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether CpG oligodeoxynucleotides (ODNs) can induce or accelerate arthritis in rats.Methods. The CpG-induced response was studied by recording joint inflammation, cell activation in draining lymph nodes, and levels of the acute-phase reactant Conclusion. We demonstrated that injection with immunostimulatory CpG, both in phosphorothioatemodified and native forms, can induce a T celldependent joint-specific inflammation in LEW and LEW.1AV1 rat strains. This arthritis is preceded by signs of activation of the innate immune system. Since unmethylated CG dinucleotides are common in bacterial DNA but rare in mammalian DNA, our results indicate that exposure to bacterial DNA during infection may contribute to arthritis induction by amplifying the innate immune response.

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Section: Discussionmentioning

(Expert classified)

Oligodeoxynucleotides containing CpG motifs can induce T cell–dependent arthritis in rats

Svelander¹,

Harris²,

Lorentzen³

et al. 2004

Arthritis & Rheumatism

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“…CpG-activated PDC indirectly activate other immune cells such as monocytes [40,41], NK cells, c/d T cells [42] and memory a/b T cells [43,44]. CpG ODN are potent humoral vaccine adjuvants in primates [45][46][47][48][49] and in humans [50].…”

Section: Introductionmentioning

confidence: 99%

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

et al. 2005

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Human Va24 + Vb11 + natural killer T cells (NKT cells) are "natural memory" T cells that detect glycolipid antigens such as a-galactosylceramide (a-GalCer) presented on CD1d.In the present study we found that highly purified Va24 + NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen a-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by a-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented a-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-a, whereas full activation of NKT cells as indicated by IFN-c production required cell-tocell contact of PDC and NKT cells in addition to IFN-a; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance a-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen. IntroductionNatural killer T (NKT) cells represent a small subset of non-conventional innate T cells with a restricted TCR repertoire for the recognition of glycolipid antigens presented on CD1d, an MHC class I-like molecule. NKT cells express markers of NK cells and exhibit an activated memory phenotype. Depending on the microenvironment and the type of stimulation, they can release large amounts of both Th1 and Th2 cytokines (especially IL-4 and IFN-c) and show cytotoxic activity in vitro (reviewed in [1][2][3]). In both mice and man NKT cells express a homologous semi-invariant TCR that in humans consists of a Va24 chain preferentially paired with a Vb11 chain [4]. In mice, NKT cells are most frequent in the liver (about 30% of hepatic T cells), bone marrow and thymus (reviewed in [5]). Smaller NKT cell populations are present in spleen and blood (reviewed in [5]). Similar to their murine counterparts, human NKT cells preferen-A. M., S. R. and V. H. equally contributed to this manuscript. tially accumulate in the liver though with a far lower frequency than in mice (4% of hepatic T cells) ([6, 7] and reviewed in [1,5]). Due to the conserved TCR, both mouse and human NKT cells recognise the same specific glycolipid antigen a-galactosylceramide (a-GalCer) when presented by CD1d molecules on antigen-presenting cells (APC) [8][9][10]. Originally isolated from a marine sponge, aGalCer was first described as an agent with strong antimetastatic activity in mice and later found to specifically activate NKT cells in a CD1d-restricted manner [8,11,12]. Glycolipid antigens similar to a-GalCer have been detected in certain bacteria and under some abnormal conditions...

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“…Activation of murine and human B cells by CpG motif containing DNA (CpG DNA) is well established (12)(13)(14). In fact, CpG motifs were discovered based on B cell stimulation (15), and B cells were the first immune cell subset in humans identified to respond to CpG DNA in a CpG-specific fashion (16,17). CpG oligodeoxynucleotides (ODN) 3 license human CD40L-primed B cells to produce high amounts of IL-12 and to support IFN-␥ production in CD4 T cells (18).…”

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confidence: 99%

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

Berkeredjian-Ding

Wagner

Hornung

et al. 2005

The Journal of Immunology

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301

215

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Detailed information of human B cell activation via TLR may lead to a better understanding of B cell involvement in autoimmunity and malignancy. In this study we identified a fundamental difference in the regulation of TLR7- and TLR9-mediated B cell stimulation: whereas the induction of polyclonal naive B cell proliferation by the TLR7 ligands resiquimod (R848) and loxoribine required the presence of plasmacytoid dendritic cells (PDCs), activation via the TLR9 ligand CpG was independent of PDCs. We found that PDC-derived type I IFN enhanced TLR7 sensitivity of B cells by selectively up-regulating TLR7 expression. In contrast the expression levels of TLR9 and of other TLRs studied remained unchanged. In the presence of type I IFN, TLR7 ligation triggered polyclonal B cell expansion and B cell differentiation toward Ig-producing plasma cells; notably, this occurred independently of T cell help and B cell Ag. Human B cells did not respond to ligands of other TLRs including TLR2, TLR4 and TLR6 with and without type I IFN. In conclusion, our results reveal a distinct regulation of TLR7 and TLR9 function in human B cells and highlight TLR7 and TLR9 as unique targets for therapeutic intervention in B cell-mediated immunity and disease.

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Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo

Cited by 540 publications

References 43 publications

Oligodeoxynucleotides containing CpG motifs can induce T cell–dependent arthritis in rats

Oligodeoxynucleotides containing CpG motifs can induce T cell–dependent arthritis in rats

CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

Plasmacytoid Dendritic Cells Control TLR7 Sensitivity of Naive B Cells via Type I IFN

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