The Experts below are selected from a list of 13215 Experts worldwide ranked by ideXlab platform
Markus F Neurath - One of the best experts on this subject based on the ideXlab platform.
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transforming growth factor beta induced foxp3 regulatory t cells suppress th1 mediated Experimental Colitis
Gut, 2006Co-Authors: Massimo C Fantini, Christoph Becker, Ingrid Tubbe, Alexei Nikolaev, Hansanton Lehr, Peter R Galle, Markus F NeurathAbstract:Background and aims: The imbalance between effector and regulatory T cells plays a central role in the pathogenesis of inflammatory bowel diseases. In addition to the thymus, CD4+CD25+ regulatory T cells can be induced in the periphery from a population of CD25− T cells by treatment with transforming growth factor β (TGF-β). Here, we analysed the in vivo function of TGF-β induced regulatory T (Ti-Treg) cells in Experimental Colitis. Methods: Ti-Treg cells were generated in cell culture in the presence or absence of TGF-β and tested for their regulatory potential in Experimental Colitis using the CD4+CD62L+ T cell transfer model. Results: Ti-Treg cells significantly suppressed Th1 mediated Colitis on CD4+CD62L+ T cell transfer in vivo, as shown by high resolution endoscopy, histology, immunohistochemistry, and cytokine analysis. Further analysis of in vivo and in vitro expanded Ti-Treg cells showed that exogenous interleukin 2 (IL-2) was crucial for survival and expansion of these cells. Conclusion: Our data suggest that regulatory Ti-Treg cells expand by TGF-β and exogenous IL-2 derived from effector T cells at the site of inflammation. In addition to Tr1 and thymic CD4+CD25+ T cells, peripheral Ti-Treg cells emerge as a class of regulatory T cells with therapeutic potential in T cell mediated chronic intestinal inflammation.
Lars Eckmann - One of the best experts on this subject based on the ideXlab platform.
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toll like receptor 9 induced type i ifn protects mice from Experimental Colitis
Journal of Clinical Investigation, 2005Co-Authors: Kyoko Katakura, Daniel Rachmilewitz, Gloria C Li, Lars EckmannAbstract:Experimental Colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of Experimental Colitis in RAG1–/– but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-α/β) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-β mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-α/β receptor exhibited more severe Colitis than wild-type mice did upon induction of Experimental Colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in Colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.
Daniel Rachmilewitz - One of the best experts on this subject based on the ideXlab platform.
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Effects of Immunostimulatory DNA Oligonucleotides on Experimental Colitis
2020Co-Authors: Daniel Rachmilewitz, Fanny Karmeli, Leonor Leider-trejo, Kenji Takabayashi, Tomoko HayashiAbstract:The etiology of human inflammatory bowel disease (IBD) is not yet known, and its pathogenesis is also poorly understood. At present, an uncontrolled or downregulated cellular immune response to an unknown trigger seems to play an important role. CD4+ T-cells were suggested to have a central role in the pathogenesis of Experimental Colitis (1) and human IBD, since in the latter, the CD4+ T cell pool is expanded both in the peripheral blood and in the inflamed mucosa (2). The balance between the three subsets of CD4+ T cells, which is well regulated under normal circumstances, is interrupted in several disease states. Human Crohn’s disease (CD) is thought to be characterized by Th-1 response, which produces IL-2, IFN-γ, and tumor necrosis factor (TNF-α). Ulcerative Colitis (UC) is dominated by Th-2 response, which produce antiinflammatory cytokines, such as; IL-4, IL-5, and IL-10. Models of Experimental Colitis also vary according to the dominant phenotype of Th-1 or Th-2 response. Spontaneous Colitis in IL-10 knockout (KO) mice is mediated predominantly by Th-1 response (3). Tri or dinitrobenzene sulphonic acid induced Colitis is characterized by predominant Th-2 response, and in this respect mimics UC (4). Administration of dextran sodium sulphate (DSS) to immune competent mice induce acute and chronic Colitis, with features characteristic of a mixed Th-1/Th-2 response (1).
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Deferiprone, an oral iron chelator, ameliorates Experimental Colitis and gastric ulceration in rats.
Inflammatory Bowel Diseases, 2007Co-Authors: Jacob N. Ablin, Oded Shalev, Fanny Karmeli, Elimelech Okon, Daniel RachmilewitzAbstract:Iron is pivotal in producing tissue-damaging reactive oxygen metabolites. Our aim is to determine the antiinflammatory activity of deferiprone, an oral iron chelator, in Experimental Colitis and gastritis. Colitis was induced by intraceccal administration of 2 ml 5% acetic acid or by intracolonic administration of 0.1 ml 3% iodoacetamide, with or without cotreatment with deferiprone. Gastritis was induced by intragastric administration of ethanol or hydrochloric acid (HCl) and by subcutaneous injection of indomethacin, with and without deferiprone. Rats were killed 24 hours after acetic acid and iodoacetamide, 30 minutes after ethanol, one hour after HCl, and three hours after indomethacin administration. The colon or stomach was isolated, macroscopic damage was measured, and mucosal samples were obtained for determination of eicosanoid generation, myeloperoxidase (MPO), and nitric oxide synthase (NOS) activities. Deferiprone decreased iodoacetamide and acetic acid-induced macroscopic colonic damage by 67% and 69%, respectively, and macroscopic gastric damage by 91%, 68%, and 46% induced by ethanol, HCl, and indomethacin, respectively. The effect of deferiprone was accompanied by significant decrease in colonic and gastric, MPO and NOS activities, and colonic prostaglandin E2 (PGE2) generation, in acetic acid, ethanol, and indomethacin models, whereas in the iodoacetamide and HCl models attenuation of the decrease in PGE2 generation was seen. Deferiprone is protective in Experimental Colitis and gastritis, probably due to decreased production of iron-dependent oxygen-free radicals. Oral iron chelators may constitute a novel approach to ameliorate gastrointestinal inflammatory disorders.
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Homeostatic effects of TLR9 signaling in Experimental Colitis.
Annals of the New York Academy of Sciences, 2006Co-Authors: Daniel RachmilewitzAbstract:: The commensal microflora of the intestinal tract confer multiple health benefits to the host, including amelioration of inflammatory bowel disease (IBD). Yet, the exact mechanisms by which it ameliorates Experimental Colitis in animals and human IBD are largely unknown. We tested whether the attenuation of Experimental Colitis by probiotic bacteria is mediated by toll-like receptor (TLR) signaling. The severity of Colitis was attenuated by delivery of nonviable, gamma-irradiated, or by viable probiotics, but not by heat-killed probiotics, in wild-type mice in mice deficient in TLR2 or TLR4. In contrast we did not observe any inhibition of Experimental Colitis by probiotics, in mice deficient in MyD88 or TLR9. Furthermore, administration of probiotic DNA ameliorated the severity of Experimental Colitis, whereas methylated probiotic DNA, calf thymus DNA, and Dnase-treated probiotics had no effect. In subsequent studies, we identified that TLR9-induced type 1 IFN mediates the anti-inflammatory effects in Experimental Colitis. The addition of neutralization antibodies to type 1 IFN abolished the anti-inflammatory effects, whereas the administration of recombinant IFN-beta mimicked the anti-inflammatory effects induced by TLR9 agonists. Taken together, these results indicate that the protective effects of probiotics are mainly mediated by their own DNA rather than by their metabolites or their ability to colonize the colon. These findings underscore the diverse effects of indigenous microbial TLR ligands in intestinal homeostasis and intestinal inflammation and suggest that strategies, that modulate type 1 IFN may be of therapeutic value for intestinal inflammatory conditions.
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toll like receptor 9 induced type i ifn protects mice from Experimental Colitis
Journal of Clinical Investigation, 2005Co-Authors: Kyoko Katakura, Daniel Rachmilewitz, Gloria C Li, Lars EckmannAbstract:Experimental Colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of Experimental Colitis in RAG1–/– but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-α/β) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-β mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-α/β receptor exhibited more severe Colitis than wild-type mice did upon induction of Experimental Colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in Colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.
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Experimental Colitis is ameliorated by inhibition of nitric oxide synthase activity.
Gut, 1995Co-Authors: Daniel Rachmilewitz, Fanny Karmeli, Elimelech Okon, M BursztynAbstract:Enhanced nitric oxide (NO) generation by stimulated NO synthase (NOS) activity may, through its oxidative metabolism contribute to tissue injury in Experimental Colitis. In this study the possible amelioration of Experimental Colitis by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS activity, was evaluated. Colitis was induced in rats by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol or by flushing the colon of capsaicin pretreated rats with 2 ml of 5% acetic acid. In several experiments, L-NAME 0.1 mg/ml was added to the drinking water at the time of Colitis induction with TNB or seven days before acetic acid treatment. Rats were killed at various time intervals after induction of Colitis. A 10 cm distal colonic segment was isolated, weighed, lesion area measured, and explants organ cultured for 24 hours for determination of NO generation by the Greiss reaction. The rest of the mucosa was scraped for determination of myeloperoxidase and NOS activities and leukotriene generation. In TNB treated rats mean arterial pressure was also determined up to 72 hours after damage induction, with or without cotreatment with nitroprusside. L-NAME significantly decreased the extent of tissue injury in TNB treated rats. Seven days after TNB treatment lesion area was reduced by 55%, colonic weight by 37%, and myeloperoxidase and NOS activity by 59% and 42%, respectively. Acetic acid induced Colitis in capsaicin pretreated rats was also significantly decreased by L-NAME. Twenty four hours after acetic acid treatment lesion area was reduced by 61%, colonic weight by 21% and NOS activity by 39%. Mean (SEM) arterial blood pressure in TNB+L-NAME treated rats was 37.6 (8.1) mm Hg higher than in TNB treated rats, an effect that was only partially abolished by nitroprusside. These results show that inhibition of NO synthesis by an L-arginine analogue significantly ameliorates the extent of tissue injury in two models of Experimental Colitis, an effect that is not due only to its vasoconstrictor properties. Modulation of NO generation may be a novel therapeutic approach in inflammatory bowel disease.
Keith A Sharkey - One of the best experts on this subject based on the ideXlab platform.
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activation of the cannabinoid 2 receptor cb2 protects against Experimental Colitis
Inflammatory Bowel Diseases, 2009Co-Authors: Martin Storr, Catherine M Keenan, Hong Zhang, Kamala D Patel, Alexandros Makriyannis, Keith A SharkeyAbstract:Background: Activation of cannabinoid (CB)1 receptors results in attenuation of Experimental Colitis. Our aim was to examine the role of CB2 receptors in Experimental Colitis using agonists (JWH133, AM1241) and an antagonist (AM630) in trinitrobenzene sulfonic acid (TNBS)-induced Colitis in wildtype and CB2 receptor-deficient (CB mice. Methods: Mice were treated with TNBS to induce Colitis and then given intraperitoneal injections of the CB2 receptor agonists JWH133, AM1241, or the CB2 receptor antagonist AM630. Additionally, CB mice were treated with TNBS and injected with JWH133 or AM1241. Animals were examined 3 days after the induction of Colitis. The colons were removed for macroscopic and microscopic evaluation, as well as the determination of myeloperoxidase activity. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for CB2 receptor was also performed in animals with TNBS and dextran sodium sulfate Colitis. Results: Intracolonic installation of TNBS caused severe Colitis. CB2 mRNA expression was significantly increased during the course of Experimental Colitis. Three-day treatment with JWH133 or AM1241 significantly reduced Colitis; AM630 exacerbated Colitis. The effect of JWH133 was abolished when animals were pretreated with AM630. Neither JWH133 nor AM1241 had effects in CB mice. Conclusions: We show that activation of the CB2 receptor protects against Experimental Colitis in mice. Increased expression of CB2 receptor mRNA and aggravation of Colitis by AM630 suggests a role for this receptor in normally limiting the development of Colitis. These results support the idea that the CB2 receptor may be a possible novel therapeutic target in inflammatory bowel disease. (Inflamm Bowel Dis 2009)
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Lack of beneficial effect of a tachykinin receptor antagonist in Experimental Colitis.
Regulatory Peptides, 1998Co-Authors: John L. Wallace, Donna-marie Mccafferty, Keith A SharkeyAbstract:Abstract Nerves within the wall of the intestine may contribute to inflammatory responses, such as those occurring in inflammatory bowel disease. Studies in an Experimental model of Colitis have demonstrated that neuromodulation, through chemical sympathectomy or administration of lidocaine, can markedly attenuate granulocyte infiltration and tissue injury. Given the many pro-inflammatory effects of substance P, we have evaluated the effects of a tachykinin receptor (NK-1) antagonist, RP 67580, in models of acute Colitis in the rat and guinea pig. While administration of RP 67580 and a second NK-1 antagonist (CP-96,345-1) significantly reduced the infiltration of granulocytes into colonic tissue during the first 12 h after induction of Colitis in the rat, repeated administration of RP 67580 over a three day period failed to significantly affect granulocyte recruitment or the severity of tissue injury. In contrast, lidocaine enemas were effective in reducing both indices of inflammation/injury. In the guinea pig, similar observations were made. These observations demonstrate that blockade of NK-1 receptors over a three day period failed to significantly modify the course of Experimental Colitis. It remains possible that the beneficial effects of lidocaine may be due, in part, to inhibition of substance P release, and that the contribution of substance P to inflammation in Experimental Colitis occurs through NK-1 receptor-independent mechanisms.
Matthew B Grisham - One of the best experts on this subject based on the ideXlab platform.
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differential angiogenic regulation of Experimental Colitis
American Journal of Pathology, 2006Co-Authors: John H Chidlow, Will Langston, James J M Greer, Dmitry V Ostanin, Maisoun Abdelbaqi, Jeffery Houghton, Annamalai Senthilkumar, Deepti Shukla, Andrew P Mazar, Matthew B GrishamAbstract:Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract with unknown multifactorial etiology that, among other things, result in alteration and dysfunction of the intestinal microvasculature. Clinical observations of increased colon microvascular density during IBD have been made. However, there have been no reports investigating the physiological or pathological importance of angiogenic stimulation during the development of intestinal inflammation. Here we report that the dextran sodium sulfate and CD4 + CD45RB high T-cell transfer models of Colitis stimulate angiogenesis that results in increased blood vessel density concomitant with increased histopathology, suggesting that the neovasculature contributes to tissue damage during Colitis. We also show that leukocyte infiltration is an obligatory requirement for the stimulation of angiogenesis. The angiogenic response during Experimental Colitis was differentially regulated in that the production of various angiogenic mediators was diverse between the two models with only a small group of molecules being similarly controlled. Importantly, treatment with the anti-angiogenic agent thalidomide or ATN-161 significantly reduced angiogenic activity and associated tissue histopathology during Experimental Colitis. Our findings identify a direct pathological link between angiogenesis and the development of Experimental Colitis, representing a novel therapeutic target for IBD.
