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CpG Oligonucleotides (cpg + oligonucleotide)
Selected AbstractsTLR9 stimulation drives naïve B cells to proliferate and to attain enhanced antigen presenting functionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2007Wei Jiang Abstract Mechanisms that regulate naïve B cell proliferation and function are incompletely defined. In this study, we test the hypothesis that naïve B cell expansion, survival and ability to present antigen to T,lymphocytes can be directly modulated by Toll-like receptor (TLR) agonists. In the absence of B cell receptor stimulation, CpG oligonucleotide, a TLR9 agonist, was particularly efficient in inducing naïve B cell proliferation and survival. Although the expanded naïve B cells did not mature into CD27+ or IgG+ memory B cells, these cells did differentiate into IgM-secreting cells with increased surface expression of HLA-DR, CD40 and CD80. This was associated with an increased potential for these B cells to activate allogeneic T cells. We propose that the activation and expansion of naïve B cells induced by TLR9 agonists could enhance the potential of these cells to interact with cognate antigens and facilitate cell-mediated immune responses. [source] Improved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: A Belgian multicentric study,GENES, CHROMOSOMES AND CANCER, Issue 10 2009Natalie Put We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12- O -tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P < 0.0001). Application of FISH (n = 201) allowed the detection of abnormalities not visible by conventional cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques. © 2009 Wiley-Liss, Inc. [source] TLR pathways and IFN-regulatory factors: To each its ownEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007Marco Colonna Abstract TLR trigger the induction of type I IFN (IFN-alpha/beta), providing a crucial mechanism of anti-viral defense. Until recently, TLR were thought to induce type I IFN responses by activating two transcription factors which belong to the IFN-regulatory factor (IRF) family, IRF-3 and IRF-7. TLR-3 and TLR-4 induce IFN-beta by activating IRF-3; TLR-9 induces IFN-alpha and IFN-beta through IRF-7, at least when engaged by type A CpG oligonucleotides (CpG-A) in plasmacytoid DC (pDC). In this issue of the European Journal of Immunology, it is demonstrated that TLR-9 induces IFN-beta when engaged by type B CpG oligonucleotides (CpG-B) in myeloid DC and macrophages. Remarkably, this response is independent of IRF-3/7 and, in fact, requires another IRF family member, IRF-1. IRF-1 is recruited by TLR-9 through the adaptor MyD88. Deficiency of the TLR-9,IRF-1,IFN-beta pathway results in impaired anti-viral responses not only in vitro but also in vivo. These results demonstrate that TLR induce IFN-alpha or IFN-beta responses by activating distinct IRF, depending on the TLR ligand and the cell type. These distinct TLR-IRF pathways may allow the immune system to tailor its responses to viral pathogens. See accompanying article http://dx.doi.org/10.1002/eji.200636767 [source] Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-, induction in plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003Gunther Hartmann Abstract Two different types of CpG motif-containing oligonucleotides (CpG ODN) have been described: CpG-A with high induction of IFN-, in plasmacytoid dendritic cells; and CpG-B with little induction of IFN-,, but potent activation of B cells. In this study, we demonstrate that CpG-A fail to activate B cells unless plasmacytoid dendritic cells are present. We identified a new set of CpG ODN sequences which induces high levels of IFN-, in plasmacytoid dendritic cells but remains capable of directly activating B cells. These new CpG ODN (termed CpG-C) are more potent stimulants of B cells than CpG-B due to their ability of directly and indirectly (via plasmacytoid dendritic cells) activating B cells. The sequence of CpG-C combines structural elements of both CpG-A and CpG-B. The most potent sequence, M362, contains a 5,-end ,TCGTCG-motif' and a ,GTCGTT-motif', both of which are present in CpG-B (ODN,2006); a palindromic sequence characteristic for CpG-A (ODN,2216); but no poly,G motif required for CpG-A. In conclusion, we defined the first CpG-containing sequences that potently activate both TLR9-expressing immune cell subsets in humans, the plasmacytoid dendritic cell and the B cell. CpG-C may allow for improved therapeutic immuno-modulation in vivo. [source] Bacteria and PAMPs activate nuclear factor ,B and Gro production in a subset of olfactory ensheathing cells and astrocytes but not in Schwann cellsGLIA, Issue 9 2007Adele J. Vincent Abstract The primary olfactory nerves provide uninterrupted conduits for neurotropic pathogens to access the brain from the nasal cavity, yet infection via this route is uncommon. It is conceivable that olfactory ensheathing cells (OECs), which envelope the olfactory nerves along their entire length, provide a degree of immunological protection against such infections. We hypothesized that cultured OECs would be able to mount a biologically significant response to bacteria and pathogen-associated molecular patterns (PAMPs). The response of OECs to Escherichia coli (E. coli) and various PAMPs was compared to that of Schwann cells (SCs), astrocytes (ACs), and microglia (MG). A subset of OECs displayed nuclear localization of nuclear factor ,B), an inflammatory transcription factor, after treatment with E. coli (20% ± 5%), lipopolysacchride (33% ± 9%), and Poly I:C (25% ± 5%), but not with peptidoglycan or CpG oligonucleotides. ACs displayed a similar level of activation to these treatments, and in addition responded to peptidoglycan. The activation of OECs and ACs was enhanced by coculture with MG (56% ± 16% and 85% ± 13%, respectively). In contrast, SCs did not respond to any treatment or to costimulation by MG. Immunostaining for the chemokine Gro demonstrated a functional response that was consistent with NF,B activation. OECs expressed mRNA for Toll-like receptors (TLRs) 2 and 4, but only TLR4 protein was detected by Western blotting and immunohistochemistry. The results demonstrate that OECs possess the cellular machinery that permits them to respond to certain bacterial ligands, and may have an innate immune function in protecting the CNS against infection. © 2007 Wiley-Liss, Inc. [source] Structure,Activity Relationship Studies on the Immune Stimulatory Effects of Base-Modified CpG Toll-Like Receptor 9 AgonistsCHEMMEDCHEM, Issue 9 2006Marion Jurk Dr. Abstract Synthetic oligodeoxynucleotides containing unmethylated deoxycytidylyl-deoxyguanosine dinucleotide (CpG) motifs are able to stimulate potent immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). We have investigated the structure,activity relationship (SAR) of base-modified CpG oligonucleotides with TLR9 by measuring TLR9 activation by 20-mer oligonucleotides having just a single human recognition motif (5,-GTCGTT-3,) in functional cell-based TLR9 assays. Substitution of guanine by hypoxanthine and 6-thioguanine resulted in activity similar to the unmodified parent molecule, whereas purine, 2-aminopurine, 2,6-diaminopurine, and 8-oxo-7,8-dihydroguanine substitution resulted in approximately 40,60,% reduction in activity, and 7-deazaguanine substitution led to the strongest (80,%) reduction in TLR9 stimulation. Furthermore, none of the investigated modifications at C5 and N4 of cytosine were well tolerated with respect to human TLR9 stimulation. Our results are compatible with a SAR model in which guanine is recognized by the Hoogsteen site, and C5 is most critical for recognition of cytosine. In addition, we found significant species-specific differences between human and murine TLR9 recognition, which demonstrates the importance of choosing appropriate assay systems for SAR studies. [source] | ||||||||||