CpG Motifs of Bacterial DNA Essentially Contribute to the Perpetuation of Chronic Intestinal Inflammation

Obermeier, Florian; Dunger, Nadja; Strauch, Ulrike; Hofmann, Claudia; Bleich, André; Grunwald, Nicole; Hedrich, Hans J.; Aschenbrenner, E; Schlegelberger, Brigitte; Rogler, Gerhard; Schölmerich, Jürgen; Falk, Werner

doi:10.1053/j.gastro.2005.06.061

Cited by 102 publications

(94 citation statements)

References 54 publications

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“…Strategies to specifically inhibit intestinal activation of TLR9 by luminal flora have recently been reported (41). These strategies consist in the use of ODNs containing immune-neutralizing motifs, which act as competitors in interaction with TLR9 (42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Calcaterra

Sfondrini²,

Rossini³

et al. 2008

The Journal of Immunology

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Graft-vs-host disease (GVHD) is a major complication after allogeneic bone marrow transplantation. Different studies have demonstrated that intestinal bacterial breakdown products and loss of gastrointestinal tract integrity, both induced by conditioning regiments, are critical in the pathogenesis of acute GVHD. Using C57BL/6 knockout mice, we evaluated the role of TLR4 and TLR9, which recognize bacterial LPS and DNA, respectively, in the GVHD associated with allogeneic bone marrow transplantation. When myeloablative-irradiated TLR9 knockout (TLR9 ؊/؊ ) mice were used as graft recipients, survival and clinical score of acute GVHD were improved as compared with the wild-type recipient mice (18/30 vs 1/31 mice still alive at day 70 in a total of four experiments); while no differences were observed using recipient TLR4 knockout (TLR4 ؊/؊ ) mice. The reduced mortality and morbidity in TLR9 ؊/؊ mice related with reduced stimulatory activity of TLR9 ؊/؊ spleen APCs after conditioning and reduced proliferation of allogeneic donor T cells. Experiments using TLR9 ؉/؉ into TLR9 ؊/؊ and TLR9 ؊/؊ into TLR9؉/؉ chimeric mice as recipients indicated a critical role for nonhematopoietic TLR9 ؉/؉ cells interacting with bacterial breakdown products released in myeloablated mice. Altogether these data reveal a novel important role of TLR9 in GVHD, a finding that might provide tools to reduce this complication of allogeneic transplantation.

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Section: Discussionmentioning

confidence: 99%

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Calcaterra

Sfondrini²,

Rossini³

et al. 2008

The Journal of Immunology

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“…[14][15][16] Bacterial genomic DNA is thus suspected to play a key role in Figure 4 BLG-specific IgG2a detection in sera of mice treated with LL(pLIG:BLG1) or LL(pLIG1). Mice were force fed 5 days consecutively with LL(pLIG:BLG1) and LL(pLIG) and again 3 weeks after the last gavage.…”

Section: Discussionmentioning

confidence: 99%

In vivo transfer of plasmid from food-grade transiting lactococci to murine epithelial cells

Pothelune

Ah‐Leung

et al. 2008

Gene Ther

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We recently demonstrated that noninvasive food-grade Lactococcus lactis (L. lactis) can deliver eukaryotic expression plasmid in mammalian cells in vitro. Here, we evaluated, in vivo, whether a eukaryotic expression plasmid carried by lactococci can translocate to the epithelial cells of the intestinal membrane. The strain LL(pLIG:BLG1) carrying one plasmid containing a eukaryotic expression cassette encoding b-lactoglobulin (BLG), a major allergen of cow's milk, was orally administered by gavage to mice. BLG cDNA was detected in the epithelial membrane of the small intestine of 40% of the mice and BLG was produced in 53% of the mice. Oral administration of LL(pLIG:BLG1) induced a low and transitory Th1-type immune response counteracting a Th2 response in case of further sensitization. We demonstrated for the first time the transfer of a functional plasmid to the epithelial membrane of the small intestine in mice by noninvasive food-grade lactococci.

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“…The sIL-15Ra induced increase in epithelial barrier dysfunction may result in a further acceleration of the previously demonstrated exaggerated immune response towards intestinal bacteria and bacterial constituents [50] in chronic DSS-induced colitis.…”

Section: Discussionmentioning

confidence: 90%

IL‐15 protects intestinal epithelial cells

et al. 2006

Self Cite

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IL‐15, a T‐cell growth factor, has been shown to be increased in inflammatory bowel disease (IBD). It has been suggested that neutralization of IL‐15 could protect from T cell‐dependent autoimmune inflammation. On the other hand, an anti‐apoptotic effect of IL‐15 has been demonstrated in kidney epithelial cells during nephritis. We therefore tested the role of IL‐15 in two different experimental models of colitis in vivo, and in models of intestinal epithelial cell (IEC) apoptosis in vitro. IL‐15 blockade in chronic dextran sulphate sodium‐induced colitis resulted in aggravation of the disease with a significantly 2.1‐fold increased epithelial damage score compared to controls. TUNEL staining clearly revealed increased apoptosis. IL‐6, TNF and IFN‐γ secretion by mesenteric lymph node cells were increased. In the T cell‐dependent SCID transfer model of colitis IL‐15 neutralization reduced the inflammatory infiltration and proinflammatory cytokine production. Despite that, the intestinal epithelial damage was not reduced. In vitro, IL‐15 pre‐incubation prevented up to 75% of CH11 antibody‐induced apoptosis in SW‐480 cells and reduced caspase‐3 activity. According to this, endogenously produced IL‐15 in chronic colitis does not only act as a proinflammatory cytokine but has at the same time the potential to reduce mucosal damage by preventing IEC apoptosis.

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CpG Motifs of Bacterial DNA Essentially Contribute to the Perpetuation of Chronic Intestinal Inflammation

Cited by 102 publications

References 54 publications

Critical Role of TLR9 in Acute Graft-versus-Host Disease

Critical Role of TLR9 in Acute Graft-versus-Host Disease

In vivo transfer of plasmid from food-grade transiting lactococci to murine epithelial cells

IL‐15 protects intestinal epithelial cells

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