Abstract:
:Bacterial, plasmid, and synthetic DNA containing unmethylated CpG dinucleotides in specific sequence contexts activate the vertebrate innate immune system. A pattern recognition receptor (PRR), toll-like receptor 9 (TLR9), recognizes CpG DNA and activates signaling cascade leading to the secretion of a number of cytokines and chemokines. Our extensive structure-immunostimulatory activity relationship studies showed that a number of synthetic pyrimidine (Y) and purine (R) nucleotides are accepted by the receptor as substitutes for natural deoxycytidine and deoxyguanosine in a CpG dinucleotide. These studies permitted development of synthetic immunostimulatory motifs YpG, CpR, and YpR and established the nucleotide motif recognition pattern of the receptor. A number of site-specific chemical modifications in the flanking sequences to the CpG dinucleotide permitted modulation of immunostimulatory affects in a predictable manner. Our studies also showed that TLR9 recognizes and reads the CpG DNA sequence from the 5'-end. Design of oligonucleotides with two 5'-ends, immunomers, resulted in potent immunomodulatory agents with distinct cytokine profiles. Immunomers containing synthetic immunostimulatory motifs produced different cytokine induction profiles compared with natural CpG motifs. Importantly, some of these synthetic motifs showed optimal activity in both mouse and human systems without requiring to change sequences, suggesting overriding the species-dependent specificity of the receptor by the use of synthetic motifs. In this article, we review current understanding of structural recognition and functional modulation of TLR9 receptor by second-generation immunomodulatory oligonucleotides and their potential application as wide spectrum therapeutic agents.
journal_name
Ann N Y Acad Scijournal_title
Annals of the New York Academy of Sciencesauthors
Agrawal S,Kandimalla ERdoi
10.1196/annals.1281.005subject
Has Abstractpub_date
2003-12-01 00:00:00pages
30-42eissn
0077-8923issn
1749-6632journal_volume
1002pub_type
杂志文章,评审abstract::In in vitro test systems, chrysotile is markedly toxic, causes chromosomal aberrations, and is capable of inducing morphological and preneoplastic transformation. In carefully designed animal experiments, chrysotile produces lung cancer and mesothelioma as effectively as do the amphiboles tested. Human population stud...
journal_title:Annals of the New York Academy of Sciences
pub_type: 杂志文章,评审
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abstract::The aim of the study was to determine the IgG antibody response to spotted fever group Rickettsia (SFGR) R. conorii and R. slovaca, and its specificity and sensitivity in patients with DEBONEL/TIBOLA. A prospective study of 31 patients with DEBONEL was carried out from January 2001 to May 2004. The SFGR serology testi...
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journal_title:Annals of the New York Academy of Sciences
pub_type: 杂志文章,评审
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abstract::Newly molted Boophilus microplus females obtained in a laboratory at 30 degrees C and environmental relative humidity (RH) were employed. An original device was used to hold ticks during feeding. Three groups of 15 ticks each were created: unfed, fed with heparinized blood, and fed with defibrinated blood. Ticks were ...
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journal_title:Annals of the New York Academy of Sciences
pub_type: 杂志文章,评审
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更新日期:1991-01-01 00:00:00
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journal_title:Annals of the New York Academy of Sciences
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journal_title:Annals of the New York Academy of Sciences
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journal_title:Annals of the New York Academy of Sciences
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journal_title:Annals of the New York Academy of Sciences
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abstract::DNA microarray analysis was conducted to investigate the transcriptional responses of the human monocytic leukemia cell line THP-1 to infection by Chlamydia trachomatis or Coxiella burnetii. RNA was isolated from mock infected cells and cells infected for 36 hours using TRIzol reagent. Biotinylated probes synthesized ...
journal_title:Annals of the New York Academy of Sciences
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journal_title:Annals of the New York Academy of Sciences
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