Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1

Branda, Richard F.; Moore, Ann L.; Mathews, Linda; McCormack, John J.; Zon, Gerald

doi:10.1016/0006-2952(93)90014-n

Cited by 114 publications

(53 citation statements)

References 17 publications

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“…All other Abs (mAbs to CD19 (B43), CD40 (5C3), CD54 (HA58), and CD86 (2331 (FUN-1)) were purchased from PharMingen (San Diego, CA). IgG1, (MOPC-21) and IgG2b, (27)(28)(29)(30)(31)(32)(35)(36)(37) were used to control for specific staining. Intracellular cytokine staining for IL-6 was performed as described (31).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…To date, the most active phosphorothioate oligonucleotide reported to stimulate human B cells is a 27-mer ODN (DSP30) originally designed as an antisense ODN to the rev gene of HIV (26 -28). A 21 mer (27) and a 15 mer (29), both 3Ј-truncated forms of the original anti-rev 27 mer, were equally active as the complete 27 mer. DSP30 contains the sequence 5Ј-TCGTCG-3Ј at its 5Ј end, suggesting the hypothesis that repeating TCG motifs may activate human B cells.…”

mentioning

confidence: 95%

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Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

Hartmann

Krieg

2000

The Journal of Immunology

541

456

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The vertebrate immune system recognizes bacterial DNA based on the presence of unmethylated CpG-dinucleotides in particular base contexts (“CpG motifs”). In contrast to mice, knowledge about CpG-mediated effects on human B cells is poor. In the present study we identify and determine an optimal human CpG motif. A phosphodiester oligonucleotide containing this motif strongly stimulated CD86, CD40, CD54, and MHC class II expression, IL-6 synthesis, and proliferation of primary human B cells. These effects required internalization of the oligonucleotide and endosomal maturation. The molecular mechanism of action of this CpG motif was associated with the sustained induction of the NF-κB p50/p65 heterodimer and of the transcription-factor complex AP-1. Transcription-factor activation by CpG DNA was preceded by increased phosphorylation of the stress kinases c-Jun N-terminal kinase and p38, and of activating transcription factor-2. In contrast to CpG, signaling through the B cell receptor led to activation of extracellular receptor kinase and to phosphorylation of a different isoform of c-Jun N-terminal kinase. These studies define the structure of a highly active human CpG motif and characterize its molecular mechanism of action in primary human B cells.

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Section: Flow Cytometrymentioning

confidence: 99%

mentioning

confidence: 95%

Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

Hartmann

Krieg

2000

The Journal of Immunology

541

456

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“…Several nucleotide sequences or motifs that exert nonspecific immunostimulatory or inhibitory effects have been identified. For example, the 27-bp ODN complementary to a portion of the rev region of the HIV gene have been shown to induce polyclonal activation of B cells in vitro (49,50) and to cause massive splenomegaly and hyper-γ-globulinemia upon in vivo administration (49). The CpG motif, originally identified in bacterial DNA (51), is now known to stimulate both humoral and cellular immune responses via acting on B cells, macrophages, dendritic cells, natural killer cells, and T cells and to control the balance between the Th1-and Th2-type immune responses (52)(53)(54)(55).…”

Section: Figurementioning

confidence: 99%

A role for NF-κB–dependent gene transactivation in sunburn

Abeyama¹,

Eng²,

Jester³

et al. 2000

J. Clin. Invest.

158

116

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“…Oligonucleotides dissolved in sterile PBS were administered s.c. to mice at a dose of 5 mg͞kg. The mice were killed after 72 h, and the spleens were harvested and weighed as described (20,21). For NF-B activation, J774 cells were plated at a density of 5 ϫ 10 6 cells per well in six-well plates and treated with oligos at a concentration of 10 g͞ml for 1 h, and nuclear extracts were prepared as described (16).…”

mentioning

confidence: 99%

A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif

Kandimalla

Bhagat

Zhu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial and synthetic DNAs containing CpG dinucleotides in specific sequence contexts activate the vertebrate immune system through Toll-like receptor 9 (TLR9). In the present study, we used a synthetic nucleoside with a bicyclic heterobase [1-(2 -deoxy-␤-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine; R] to replace the C in CpG, resulting in an RpG dinucleotide. The RpG dinucleotide was incorporated in mouse-and human-specific motifs in oligodeoxynucleotides (oligos) and 3 -3-linked oligos, referred to as immunomers. Oligos containing the RpG motif induced cytokine secretion in mouse spleen-cell cultures. Immunomers containing RpG dinucleotides showed activity in transfected-HEK293 cells stably expressing mouse TLR9, suggesting direct involvement of TLR9 in the recognition of RpG motif. In J774 macrophages, RpG motifs activated NF-B and mitogen-activated protein kinase pathways. Immunomers containing the RpG dinucleotide induced high levels of IL-12 and IFN-␥, but lower IL-6 in time-and concentrationdependent fashion in mouse spleen-cell cultures costimulated with IL-2. Importantly, immunomers containing GTRGTT and GARGTT motifs were recognized to a similar extent by both mouse and human immune systems. Additionally, both mouse-and humanspecific RpG immunomers potently stimulated proliferation of peripheral blood mononuclear cells obtained from diverse vertebrate species, including monkey, pig, horse, sheep, goat, rat, and chicken. An immunomer containing GTRGTT motif prevented conalbumin-induced and ragweed allergen-induced allergic inflammation in mice. We show that a synthetic bicyclic nucleotide is recognized in the C position of a CpG dinucleotide by immune cells from diverse vertebrate species without bias for flanking sequences, suggesting a divergent nucleotide motif recognition pattern of TLR9.T he immune system of vertebrates recognizes synthetic oligodeoxynucleotides, bacterial and plasmid DNAs containing unmethylated CpG dinucleotides in specific sequence contexts (CpG motifs) (1-5). This recognition is mediated by a molecular pattern recognition receptor, Toll-like receptor 9 (TLR9) (6). Upon activation by CpG DNA, TLR9 initiates signaling pathways that activate several transcription factors, including NF-B and AP-1 (3-5). The immunological events that occur after CpG DNA activation of the immune system include B cell proliferation, increased expression of MHC class II antigens, increased synthesis of RNA and DNA, and the release of a number of cytokines and chemokines (7-9). The potent T helper 1 immune response produced by CpG activation of the innate immune system supports the broad therapeutic application of CpG DNA against cancer, infectious diseases, asthma, and allergies and as adjuvants in immunotherapy. Several studies have demonstrated the potential effectiveness of CpG DNAs as therapies in animal models, and a number of CpG DNAs are currently being tested in clinical trials (4, 10).We previously showed that two CpG DNAs attached through their 5Ј ends failed to stimulate the immune syst...

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Immune stimulation by an antisense oligomer complementary to the rev gene of HIV-1

Cited by 114 publications

References 17 publications

Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

Mechanism and Function of a Newly Identified CpG DNA Motif in Human Primary B Cells

A role for NF-κB–dependent gene transactivation in sunburn

A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif

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