Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells

Decker, Thomas; Schneller, Folker; Kronschnabl, Manuela; Dechow, Tobias; Lipford, Grayson B.; Wagner, Hermann; Peschel, Christian

doi:10.1016/s0301-472x(00)00144-2

Cited by 89 publications

(78 citation statements)

References 43 publications

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“…Immunomers containing the RpG motif induced cells to rapidly produce high levels of cytokines compared with conventional linear CpG oligos, as determined in kinetics studies using IL-2 as a costimulator (31). In general, activation of immune cells with RpG immunomers resulted in higher IL-12 and IFN-␥ than that occurred with CpG oligos (Fig.…”

Section: Discussionmentioning

confidence: 78%

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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Section: Discussionmentioning

confidence: 78%

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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“…By contrast, TNF-α and IL-6 production was increased in CLL cells, and the expression of CD80 and CD86 was further augmented when IL-2 was used as a costimulus. Autologous and allogeneic immune recognition of CLL B cells stimulated with CpG-ODN and IL-2 was increased compared with CLL B cells stimulated with CpG-ODN alone [102]. Furthermore, synthetic TLR9 ligands (oligodeoxynucleotides, ODN) bear the potential to enhance the immunogenicity of B-CLL cells by upregulation of CD25, a target for immunotoxin LMB-2.…”

Section: The Results Of Tlr Activation -Tlrs In Carcinogenesismentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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“…These approaches include gene therapy 14,15 , CD40 ligation, and 14-17 treatment with cytokines 18 or immunostimulatory oligonucleotides (CpG ODN). [19][20][21][22] Based on this background, and the fact that FISH can be performed easily in B-CLL, we explored the relationship between the cytogenetic status of B-CLL cells and their tendency to undergo apoptosis in vitro. We also explored the impact of cytogenetic status on the immunogenicity of the B-CLL cells.…”

Section: Introductionmentioning

confidence: 99%

Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity

et al. 2005

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Chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) have been shown to correlate with prognosis. Little is known about the relationship between chromosomal abnormalities and biological behavior of B-CLL cells in vitro. The present study was designed to explore the impact of chromosomal abnormalities determined by interphase fluorescence in situ hybridization (FISH) on the in vitro survival and immunogenicity of B-CLL. Considerable heterogeneity was noted in the in vitro survival and expression of costimulatory, adhesion, and antigen-presenting molecules by B-CLL cells. Spontaneous apoptosis of B-CLL cells in vitro was significantly lower in samples with good prognosis cytogenetics when compared to samples with poor prognosis cytogenetics. In contrast, B-CLL cells from samples with good prognosis cytogenetics exhibited higher basal expression of molecules involved in costimulation, cellular adhesion, and antigen presentation, and induced significantly more T-cell proliferation in mixed lymphocyte cultures. We conclude that chromosomal aberrations of B-CLL cells correlate with the in vitro biological behavior of B-CLL. Our data indicate that good prognosis cytogenetics correlates with less spontaneous apoptosis but greater in vitro immunogenicity. These findings could have significant implications on the design of future therapeutic approaches in patients with CLL, and the likelihood of response based on cytogenetics.

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Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells

Cited by 89 publications

References 43 publications

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

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

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity

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