Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus‐prone NZB × NZW mice

Dong, Li; Ito, Shuichi; Ishii, Ken J.; Klinman, Dennis M.

doi:10.1002/art.20810

Cited by 133 publications

(141 citation statements)

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“…Therefore, targeting TLR signaling pathways may be an effective way to treat autoimmune disease, and support for this approach exists: the pharmacological effect of chloroquines -used to treat SLE since the 1950s [61] -may be due to inhibition of the lysosome acidification required for TLR7, TLR8 and TLR9 signaling [28,62], and oligonucleotides with suppressive effects on TLR signaling have been successfully used to prevent development of murine lupus in (NZBÂNZW)F 1 mice [63]. Future studies are required to strengthen the association between TLR signaling and SLE, and to identify more efficient TLR-targeted treatments.…”

Section: Discussionmentioning

confidence: 99%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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Section: Discussionmentioning

confidence: 99%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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“…Previous reports demonstrated that suppressive ODN of the A151 class can down-regulate Th1 responses induced by a variety of immune stimuli (12)(13)(14)(15)(16)(17)(18)(19). The current results establish that these ODN dampen Th1 signaling by binding to and preventing the phosphorylation of STAT1 and STAT4, thereby reducing the production of IFN-␥, a cytokine critical to the maintenance of Th1 immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Several recent reports indicate that suppressive oligonucleotides (ODN) 3 are capable of blocking the deleterious production of Th1 and proinflammatory cytokines (12)(13)(14)(15)(16)(17)(18)(19). One class of suppressive ODN is characterized by the presence of methylated CG or unmethylated GC sequences that selectively block CpG-induced immune activation (20 -24).…”

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confidence: 99%

“…The second class of suppressive ODN contains repetitive TTAGGG motifs patterned after those present in mammalian telomeres (12). Previous studies established that telomeric DNA and suppressive ODN containing TTAGGG motifs down-regulate the production of proinflammatory and Th1 cytokines (12)(13)(14)(15). Although initially identified by their ability to block CpG-induced immune activation, this class of suppressive ODN (typified by ODN A151) was subsequently shown to block multiple forms of immune stimulation (14 -19) and to be effective in the prevention/treatment of pathologic autoimmune responses (13,15,25).…”

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confidence: 99%

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Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

Shirota

Gürsel

et al. 2005

The Journal of Immunology

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122

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Endotoxic shock is a life-threatening condition caused by exposure to bacterial LPS. LPS triggers the release of acute phase, proinflammatory, and Th1 cytokines that facilitate the development of endotoxic shock. Synthetic oligodeoxynucleotides (ODN) expressing suppressive TTAGGG motifs effectively down-regulate the production of proinflammatory and Th1 cytokines elicited by a variety of immune stimuli. The current results demonstrate that suppressive ODN protect mice from LPS-induced endotoxic shock. Underlying this protective effect is the ability of suppressive ODN to bind to and prevent the phosphorylation of STAT1 and STAT4, thereby blocking the signaling cascade mediated by LPS-induced IFN-β and IL-12. These findings suggest that suppressive ODN might be of use in the treatment of endotoxic shock.

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“…Besides blocking Fc␥RIIa by specific antibodies (20), the TLRs involved in IFN␣ gene activation by such immune complexes could be inhibited by TLR antagonists in the form of oligodeoxynucleotides (ODNs) or oligoribonucleotides. In fact, treatment of lupus-prone mice with suppressive ODNs prolonged their survival (113), but the effects on the type I IFN system was not extensively investigated. Several of the signaling molecules downstream of the TLRs, such as MyD88, IL-1 receptor-associated kinase 1, IRF-5, and IRF-7, remain to be investigated as therapeutic targets in SLE (55,114,115).…”

Section: Therapeutic Consequencesmentioning

confidence: 99%