The Experts below are selected from a list of 1365 Experts worldwide ranked by ideXlab platform
Zhiren Zhang - One of the best experts on this subject based on the ideXlab platform.
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Lesional accumulation of CD8+ cells in sciatic nerves of Experimental Autoimmune Neuritis rats
Neurological Sciences, 2015Co-Authors: Zhi-ming Zhang, Hong Chen, Zhiren ZhangAbstract:Experimental Autoimmune Neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies. Macrophages are the major immune cells in peripheral nerves and may exert tissue-damage or tissue-protective activity during EAN. While considered to define a subpopulation of T lymphocytes, CD8 expression has been found on certain macrophages that show cytotoxic effects. Here we have studied the spatiotemporal accumulation of CD8+ cells in sciatic nerves of EAN rats. A robust accumulation of CD8+ cells was observed in the sciatic nerves of EAN rats, which was positively correlated with the severity of neurological signs in EAN. Moreover, double-labelling experiments showed that the major cellular sources of CD8 were reactive macrophages. Therefore, our data here suggest a pathological role of CD8+ macrophages in EAN, which makes CD8+ macrophage a potential therapeutic target for EAN.
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curcumin ameliorates rat Experimental Autoimmune Neuritis
Journal of Neuroscience Research, 2014Co-Authors: Zhonghao Zhang, Jian Xiong, Man Jiang, Zhiren ZhangAbstract:Experimental Autoimmune Neuritis (EAN) is a helper T cell-mediated Autoimmune demyelinating inflammatory disease of the peripheral nervous system that serves as an animal model for human Guillain-Barre syndrome. Curcumin, a naturally occurring polyphenolic phytochemical isolated from the medicinal plant Curcuma longa, has anti-inflammatory activities. Here we investigated the therapeutic effects and potential mechanisms of curcumin in EAN rats. Exogenous curcumin treatment (100 mg/kg/day) significantly delayed the onset of EAN neurological signs, ameliorated EAN neurological severity, and reduced body weight loss of EAN rats. In EAN sciatic nerves, curcumin treatment suppressed the inflammatory cell accumulation and the expression of interferon (IFN)-γ, tumor necrosis factor-α, interleukin (IL)-1β, and IL-17. Furthermore, curcumin treatment significantly decreased the percentage of CD4+ T helper cells in EAN spleen and suppressed concanavalin A-induced lymphocyte proliferation in vitro. In addition, curcumin altered helper T cell differentiation by decreasing IFN-γ+CD4+ Th1 cells in EAN lymph node and spleen. In summary, our data demonstrate that curcumin could effectively suppress EAN by attenuating inflammation, indicating that curcumin might be a candidate for treatment of Autoimmune neuropathies. © 2014 Wiley Periodicals, Inc.
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Accumulation of Fascin(+) cells during Experimental Autoimmune Neuritis
Diagnostic Pathology, 2013Co-Authors: Zichen Yang, Xiaofeng Yang, Zhi-yuan Zhang, Jian Xiong, Hermann J. Schluesener, Zhiren ZhangAbstract:Background Experimental Autoimmune Neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Fascin is an evolutionarily highly conserved cytoskeletal protein of 55 kDa containing two actin binding domains that cross-link filamentous actin to hexagonal bundles.
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distinct expression of tim 3 during different stages of rat Experimental Autoimmune Neuritis
Brain Research Bulletin, 2011Co-Authors: Zhi-yuan Zhang, Hermann J. Schluesener, Zhiren ZhangAbstract:Abstract Experimental Autoimmune Neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Tim-3 had been identified as a Th1-specific marker negatively regulating autoimmunity or inflammatory diseases. Here we have studied by immunohistochemistry the spatiotemporal accumulation of Tim-3+ cells in sciatic nerves of EAN rats, particularly focusing on its association with alternatively activated macrophages. Our results showed that time course of Tim-3+ cell accumulation correlated positively with disease progression of EAN; but distinct major cellular resources of Tim-3 were observed at different disease stages of EAN: during the early phase of EAN, the main cellular resource were T cells, but at the peak and during recovery phase of EAN, Tim-3 was mostly expressed on CD68+ macrophages or CD163+ cells. Further investigation suggested that accumulation of CD163+ cells, particularly their relative abundances to activated macrophages at different time points, were in accordance with the recovery from EAN. Therefore, Tim3+ cells might include a distinct macrophage population, which may be involved in anti-inflammatory effect and recovery from EAN.
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doxycycline attenuates peripheral inflammation in rat Experimental Autoimmune Neuritis
Neurochemical Research, 2011Co-Authors: Zhi-yuan Zhang, Hermann J. Schluesener, Zhiren Zhang, Chenju Yi, Wei WangAbstract:Experimental Autoimmune Neuritis (EAN) is a T cell-mediated Autoimmune inflammatory demyelinating disease of the peripheral nervous system and widely-used animal model of human inflammatory demyelinating polyradiculoneuropathies. Doxycycline is a well-known antibiotic and has been reported to have neuroprotective and anti-inflammatory effects. Here we investigated the effects of doxycycline on rat EAN. Therapeutic treatment with doxycycline (40 mg/kg body weight daily from the Day 9 to Day 14 post immunization) significantly attenuated the severity of EAN, decreased inflammatory infiltration of macrophages, B- and T-cells and demyelination in sciatic nerves of EAN rats. Pro-inflammatory molecules including matrixmetalloproteinase-9, inducible nitric oxide synthase and interleukin-17 were greatly decreased in sciatic nerves by administration of doxycycline as well. Taken together, our data showed that doxycycline could effectively suppress the peripheral inflammation to improve outcome of EAN, which suggests that doxycycline may be considered as a potential candidate of pharmacological treatment for neuropathies.
Ralf Gold - One of the best experts on this subject based on the ideXlab platform.
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anti inflammatory and immunomodulatory potential of human immunoglobulin applied intrathecally in lewis rat Experimental Autoimmune Neuritis
Journal of Neuroimmunology, 2017Co-Authors: Kalliopi Pitarokoili, Ralf Gold, Xiomara Pedreiturria, Jeremias Motte, Felix Kohle, Oluwaseun Fatoba, Minsuk YoonAbstract:Abstract Intravenous human immunoglobulins dominate in the treatment of Autoimmune neuropathies. We introduce intrathecal application as a new option for Experimental Autoimmune Neuritis in Lewis rats. After immunisation with neuritogenic P2 peptide, we show a therapeutic and preventive effect of intrathecal human immunoglobulins (5–40 mg/kg) on clinical and electrophysiological Neuritis signs. Histology corroborated a lower degree of inflammation, demyelination, ICAM-1-dependent blood-nerve-barrier permeability and complement activation in the sciatic nerve. After preventive application, immunoglobulins induced a Th2 cytokine shift in the peripheral nerves already before clinical Neuritis signs. Intrathecal immunoglobulin application could be a novel immunomodulatory option for Autoimmune neuropathies.
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fingolimod attenuates Experimental Autoimmune Neuritis and contributes to schwann cell mediated axonal protection
Journal of Neuroinflammation, 2017Co-Authors: Bjorn Ambrosius, Kalliopi Pitarokoili, Lisa Schrewe, Xiomara Pedreiturria, Jeremias Motte, Ralf GoldAbstract:Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral Autoimmune neuropathies are lacking. We tested fingolimod in the animal model of Experimental Autoimmune Neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod. Histology of the sciatic nerve was done to analyze T cell and macrophage cell count, intercellular adhesion molecule (ICAM) and amyloid precursor protein (APP) expression, as well as apoptotic Schwann cell counts. Preventive oral treatment with 0.1 mg/kg up to 3 mg/kg fingolimod once daily dissolved in rapeseed oil completely ameliorated clinical Neuritis signs. It reduced circulating peripheral blood T cells and infiltrating T cells and macrophages in the sciatic nerve, whereas at the same time, it preserved blood-nerve barrier impermeability. Most importantly, fingolimod showed beneficial properties on the pathogenic process as indicated by fewer apoptotic Schwann cells and a lower amount of amyloid precursor protein indicative of axonal damage at the peak of disease course. Taken together, orally administered low-dose fingolimod showed an impressive immunomodulatory effect in the rat model of Experimental Autoimmune Neuritis. Our current observations introduce fingolimod as an attractive treatment option for Neuritis patients.
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neuroprotective effects of laquinimod in lewis rat Experimental Autoimmune Neuritis p4 107
Neurology, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Michael R Hayden, Liat Hayardeny Nisimov, Ralf GoldAbstract:OBJECTIVE:We investigated the neuroprotective effect of laquinimod (LQ) in Experimental Autoimmune Neuritis (EAN), a rat model of acute Autoimmune peripheral polyNeuritis (Guillain-Barre Syndrome). BACKGROUND:LQ is an orally administered, active immunomodulator with neuroprotective potential in phase 3 studies for patients with multiple sclerosis. It induces overexpression of brain-derived neurotrophic factor (BDNF) in the cortex of mice with Experimental Autoimmune encephalomyelitis (EAE), the model of multiple sclerosis. DESIGN/METHODS:Active EAN was induced by immunization with the peptide aa 53-78 of P2 myelin protein in Lewis rats followed by oral treatment with 12.5 mg/kg or 25 mg/kg LQ daily from day 1 to day 28 post-immunisation (p.i.), and clinical score was assessed daily. Histological analyses of the sciatic nerves regarding demyelination and early axonal damage (amyloid precursor protein, APP staining), inflammatory infiltrates and Schwann cells survival (TUNEL staining), and BDNF expression were performed at the disease maximum (day 16 p.i.). RESULTS:Treatment with 12.5 mg/kg LQ completely abolished clinical Neuritis, and histology corroborated a lower degree of T cells and macrophages infiltration and demyelination in the peripheral nerves. Furthermore, we observed a reduction of early axonal damage, as implied by APP staining (p<0.0005, n=6). The histological analysis showed an increase of BDNF-producing Schwann cells (35[percnt] of BDNF-positive Schwann cells per slide for sham treated group as opposed to 50[percnt] for 12.5mg/kg/day laquinimod treated group p<0.005, n=6), with a coincidental improvement of Schwann cell survival (mean numbers of TUNEL+ Schwann cells 10/sciatic nerve section for sham treated rats, 3/sciatic nerve section for 12.5mg/kg/day laquinimod treated rats, p<0.005, n=6) in the sciatic nerves of laquinimod treated rats. CONCLUSIONS:LQ ameliorated Experimental Autoimmune Neuritis showing a neuroprotective potential by reducing early axonal damage in sciatic nerves, possibly through an increase of BDNF-producing Schwann cells in the peripheral nerves. Disclosure: Dr. Pitarokoili has nothing to disclose. Dr. Ambrosius has nothing to disclose. Dr. Schrewe has nothing to disclose. Dr. Hayardeny Nisimov has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Hayden has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Gold has received personal compensation for activities with Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience.
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Neuroprotective Effects of Laquinimod in Lewis Rat Experimental Autoimmune Neuritis (P4.107)
Neurology, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Michael R Hayden, Liat Hayardeny Nisimov, Ralf GoldAbstract:OBJECTIVE:We investigated the neuroprotective effect of laquinimod (LQ) in Experimental Autoimmune Neuritis (EAN), a rat model of acute Autoimmune peripheral polyNeuritis (Guillain-Barre Syndrome). BACKGROUND:LQ is an orally administered, active immunomodulator with neuroprotective potential in phase 3 studies for patients with multiple sclerosis. It induces overexpression of brain-derived neurotrophic factor (BDNF) in the cortex of mice with Experimental Autoimmune encephalomyelitis (EAE), the model of multiple sclerosis. DESIGN/METHODS:Active EAN was induced by immunization with the peptide aa 53-78 of P2 myelin protein in Lewis rats followed by oral treatment with 12.5 mg/kg or 25 mg/kg LQ daily from day 1 to day 28 post-immunisation (p.i.), and clinical score was assessed daily. Histological analyses of the sciatic nerves regarding demyelination and early axonal damage (amyloid precursor protein, APP staining), inflammatory infiltrates and Schwann cells survival (TUNEL staining), and BDNF expression were performed at the disease maximum (day 16 p.i.). RESULTS:Treatment with 12.5 mg/kg LQ completely abolished clinical Neuritis, and histology corroborated a lower degree of T cells and macrophages infiltration and demyelination in the peripheral nerves. Furthermore, we observed a reduction of early axonal damage, as implied by APP staining (p
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laquinimod exerts strong clinical and immunomodulatory effects in lewis rat Experimental Autoimmune Neuritis
Journal of Neuroimmunology, 2014Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Liat Hayardeny, Michael R Hayden, Ralf GoldAbstract:Abstract Laquinimod is an immunomodulatory drug with neuroprotective potential. We used the animal model of Experimental Autoimmune Neuritis (EAN) in the Lewis rat to study the effects of laquinimod treatment. After immunization with the neuritogenic peptide aa 53–78 of P2 myelin protein, preventive therapy with 12.5 mg/kg laquinimod once daily inhibited Neuritis in clinical and electrophysiological terms. Histology corroborated a lower degree of inflammatory lesions and demyelination in the sciatic nerve. The proportion of FoxP3-positive regulatory T cells in the peripheral lymph nodes of treated rats remained unchanged. We conclude that laquinimod may represent a therapeutic option in human Autoimmune neuropathies.
Hermann J. Schluesener - One of the best experts on this subject based on the ideXlab platform.
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Accumulation of Fascin(+) cells during Experimental Autoimmune Neuritis
Diagnostic Pathology, 2013Co-Authors: Zichen Yang, Xiaofeng Yang, Zhi-yuan Zhang, Jian Xiong, Hermann J. Schluesener, Zhiren ZhangAbstract:Background Experimental Autoimmune Neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Fascin is an evolutionarily highly conserved cytoskeletal protein of 55 kDa containing two actin binding domains that cross-link filamentous actin to hexagonal bundles.
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distinct expression of tim 3 during different stages of rat Experimental Autoimmune Neuritis
Brain Research Bulletin, 2011Co-Authors: Zhi-yuan Zhang, Hermann J. Schluesener, Zhiren ZhangAbstract:Abstract Experimental Autoimmune Neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Tim-3 had been identified as a Th1-specific marker negatively regulating autoimmunity or inflammatory diseases. Here we have studied by immunohistochemistry the spatiotemporal accumulation of Tim-3+ cells in sciatic nerves of EAN rats, particularly focusing on its association with alternatively activated macrophages. Our results showed that time course of Tim-3+ cell accumulation correlated positively with disease progression of EAN; but distinct major cellular resources of Tim-3 were observed at different disease stages of EAN: during the early phase of EAN, the main cellular resource were T cells, but at the peak and during recovery phase of EAN, Tim-3 was mostly expressed on CD68+ macrophages or CD163+ cells. Further investigation suggested that accumulation of CD163+ cells, particularly their relative abundances to activated macrophages at different time points, were in accordance with the recovery from EAN. Therefore, Tim3+ cells might include a distinct macrophage population, which may be involved in anti-inflammatory effect and recovery from EAN.
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doxycycline attenuates peripheral inflammation in rat Experimental Autoimmune Neuritis
Neurochemical Research, 2011Co-Authors: Zhi-yuan Zhang, Hermann J. Schluesener, Zhiren Zhang, Chenju Yi, Wei WangAbstract:Experimental Autoimmune Neuritis (EAN) is a T cell-mediated Autoimmune inflammatory demyelinating disease of the peripheral nervous system and widely-used animal model of human inflammatory demyelinating polyradiculoneuropathies. Doxycycline is a well-known antibiotic and has been reported to have neuroprotective and anti-inflammatory effects. Here we investigated the effects of doxycycline on rat EAN. Therapeutic treatment with doxycycline (40 mg/kg body weight daily from the Day 9 to Day 14 post immunization) significantly attenuated the severity of EAN, decreased inflammatory infiltration of macrophages, B- and T-cells and demyelination in sciatic nerves of EAN rats. Pro-inflammatory molecules including matrixmetalloproteinase-9, inducible nitric oxide synthase and interleukin-17 were greatly decreased in sciatic nerves by administration of doxycycline as well. Taken together, our data showed that doxycycline could effectively suppress the peripheral inflammation to improve outcome of EAN, which suggests that doxycycline may be considered as a potential candidate of pharmacological treatment for neuropathies.
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auy954 a selective s1p1 modulator prevents Experimental Autoimmune Neuritis
Journal of Neuroimmunology, 2009Co-Authors: Zhi-yuan Zhang, Zhiren Zhang, Barbara Nuessleinhildesheim, David Leppert, Hermann J. SchluesenerAbstract:Abstract Experimental Autoimmune Neuritis (EAN) is a T cell-mediated Autoimmune inflammatory demyelinating disease of the peripheral nervous system and an animal model of human inflammatory demyelinating polyradiculoneuropathy. AUY954, which targets selectively the sphingosine-1-phosphate receptor 1 (S1P 1 ), is known to sequester lymphocytes into secondary lymphoid tissues. In EAN rats, AUY954 greatly prevented paraparesis if administrated from the day of immunization. T cell, B cell, and macrophage infiltration, inflammatory demyelination, and local expression of interleukine-17 and matrix metalloproteinase-9 in sciatic nerves of EAN rats were significantly decreased by AUY954 treatment. Therefore, S1P 1 modulation might be a potential treatment option for inflammatory neuropathies.
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distribution of foxp3 t regulatory cells in Experimental Autoimmune Neuritis rats
Experimental Neurology, 2009Co-Authors: Zhiren Zhang, Zhi-yuan Zhang, Uwe Fauser, Hermann J. SchluesenerAbstract:Abstract T-regulatory cells expressing the forkhead box transcription factor 3 (Foxp3) play essential roles in immune homeostasis. Experimental Autoimmune Neuritis (EAN) is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. We investigated the distribution of Foxp3 + cells in sciatic nerves, spleen and lymph nodes of EAN rats, and the influence of FTY720 on the localization of Foxp3 + cells in EAN rats. In sciatic nerves of EAN rats, accumulation of Foxp3 + cells was not seen during the pre-symptomatic phase (until Day 9) or during early or peak disease activity. In contrast, Foxp3 + cell accumulation was regularly seen in the recovery from neurologic disease, suggesting a contribution of Foxp3 + cells to the resolution of EAN. FTY720 was given at onset of EAN (Day 10) until Day 18. Following FTY720 administration, percentages of Foxp3 + cells in EAN rats were increased in circulating blood, but reduced in lymph nodes compared to the PBS control. FTY720 treatment suppressed total numbers but increased percentages of Foxp3 + cells in sciatic nerves of EAN rats. These data not only suggests a protective role of Foxp3 + cells in EAN but also provides a potential way to alter localization of Foxp3 + cells in vivo.
Klaus V. Toyka - One of the best experts on this subject based on the ideXlab platform.
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treatment and prevention of Experimental Autoimmune Neuritis with superagonistic cd28 specific monoclonal antibodies
Journal of Neuroimmunology, 2003Co-Authors: Jens Schmidt, Klaus V. Toyka, Ralf Gold, Karin Elflein, M Stienekemeier, Marta Rodriguezpalmero, C Schneider, Thomas HunigAbstract:Abstract Two distinct CD28-specific mAb were used in treatment of active or adoptive transfer (AT)-Experimental Autoimmune Neuritis (EAN): “superagonistic” JJ316 activates T cells without T cell receptor (TCR) occupancy, and conventional JJ319 activates T cells only in the presence of TCR-stimulation. Treatment with JJ316 during induction phase of active and adoptive-transfer Experimental Autoimmune encephalomyelitis (AT-EAN) dramatically reduced disease severity and improved nerve function as revealed by electrophysiology. JJ316 given 1 week before immunization had a preventive effect. By immunohistology, JJ316 markedly reduced TC infiltration of the sciatic nerve in active and AT-EAN. JJ319 was less effective. Ex vivo, JJ316 therapy reduced P2-specific proliferation and interferon-γ (IFN-γ) production of lymph node cells. We demonstrate preventive and therapeutic effects of a “superagonistic” mAb-mediated, TCR-independent CD28 stimulation in EAN, possibly with implications for therapy of Autoimmune-inflammatory disorders.
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suppression of Experimental Autoimmune Neuritis by leflunomide
Brain, 2001Co-Authors: Thomas Korn, Hans-peter Hartung, Klaus V. Toyka, Stefan JungAbstract:Summary Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis. Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways. We investigated the immunosuppressive effects of leflunomide in Experimental Autoimmune Neuritis (EAN) in rats, which is a model of immune-mediated neuropathies. In EAN that was actively induced by subcutaneous injection of peripheral nerve myelin, leflunomide completely prevented paraparesis if applied orally from the day of immunization. Leflunomide was much more effective than azathioprine, which did not mitigate EAN at all. Even when leflunomide was administered therapeutically after the appearance of the first neuropathical signs, it halted the progression and markedly reduced the severity and duration of EAN. Inflammatory infiltrates, demyelination and axonal degeneration in sciatic nerve sections of leflunomide-treated EAN rats were strongly reduced. Leflunomide-treated rats did not mount
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sequential expression of chemokines in Experimental Autoimmune Neuritis
Journal of Neuroimmunology, 2000Co-Authors: Bernd C Kieseier, Klaus V. Toyka, Stefan Jung, Kimberly Krivacic, Heidrun Pischel, Richard M Ransohoff, Hans-peter HartungAbstract:Abstract Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-γ-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced Experimental Autoimmune Neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1α and MIP-1β were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.
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Failure of intravenous immunoglobulin (IVIg) therapy in Experimental Autoimmune Neuritis (EAN) of the Lewis rat.
Journal of Neuroimmunology, 1997Co-Authors: U Enders, Klaus V. Toyka, H P Hartung, R GoldAbstract:Abstract Experimental Autoimmune Neuritis (EAN) is an animal model for Guillain-Barre syndrome (GBS). Intravenous immunoglobulins (IVIg) are an effective treatment for GBS, but their mechanism of action is not well understood. Here we tested whether IVIg treatment, a potent modulator of proinflammatory assaults, reduces inflammation in EAN. The evaluation of IVIg treatment failed to demonstrate a salutary effect in different models of EAN. IVIg appears not to suppress the acute inflammatory insult on the peripheral nerve, but may have beneficial long-term effects not looked for in the present investigation.
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antigen therapy eliminates t cell inflammation by apoptosis effective treatment of Experimental Autoimmune Neuritis with recombinant myelin protein p2
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Andreas Weishaupt, Hans-peter Hartung, Ralf Gold, Stefanie Gaupp, Gerhard Giegerich, Klaus V. ToykaAbstract:Exposure of T cells to their specific antigen normally results in proliferation, but in the presence of high and repeatedly administered doses of antigen, T cells may undergo apoptosis. Here we demonstrate that i.v. administration of as little as 100 μg of recombinant P2 protein twice daily completely prevents Experimental Autoimmune Neuritis induced by adoptive transfer of neuritogenic P2-specific T cells or by immunization with the neuritogenic P2–peptide-spanning amino acids 53–78. Antigen treatment started after disease onset markedly ameliorated Experimental Autoimmune Neuritis. The mechanism of action may be through programmed T cell death; a profound increase of the rate of apoptosis was seen in inflammatory foci of peripheral nerves and in the spleen. There was no cytokine switch by our Th1 cells after exposure to their specific antigen, but increased secretion of interferon γ and tumor necrosis factor α was demonstrated. High antigen dose therapy using recombinant, pathogen-free protein may prove useful for the treatment of Autoimmune inflammatory disorders of the nervous system.
Hans-peter Hartung - One of the best experts on this subject based on the ideXlab platform.
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quinpramine ameliorates rat Experimental Autoimmune Neuritis and redistributes mhc class ii molecules
PLOS ONE, 2011Co-Authors: Gerd Meyer Zu Horste, Hans-peter Hartung, Helmar C. Lehmann, Anne K Mausberg, Johanna I Muller, Stefan Lober, Peter Gmeiner, Olaf Stuve, Carsten Korth, Bernd C KieseierAbstract:Activation of inflammatory cells is central to the pathogenesis of Autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine—generated from imipramine and quinacrine—redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat Experimental Autoimmune Neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barre syndrome. EAN animals develop paresis of all limbs due to Autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies.
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suppression of Experimental Autoimmune Neuritis by leflunomide
Brain, 2001Co-Authors: Thomas Korn, Hans-peter Hartung, Klaus V. Toyka, Stefan JungAbstract:Summary Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis. Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways. We investigated the immunosuppressive effects of leflunomide in Experimental Autoimmune Neuritis (EAN) in rats, which is a model of immune-mediated neuropathies. In EAN that was actively induced by subcutaneous injection of peripheral nerve myelin, leflunomide completely prevented paraparesis if applied orally from the day of immunization. Leflunomide was much more effective than azathioprine, which did not mitigate EAN at all. Even when leflunomide was administered therapeutically after the appearance of the first neuropathical signs, it halted the progression and markedly reduced the severity and duration of EAN. Inflammatory infiltrates, demyelination and axonal degeneration in sciatic nerve sections of leflunomide-treated EAN rats were strongly reduced. Leflunomide-treated rats did not mount
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sequential expression of chemokines in Experimental Autoimmune Neuritis
Journal of Neuroimmunology, 2000Co-Authors: Bernd C Kieseier, Klaus V. Toyka, Stefan Jung, Kimberly Krivacic, Heidrun Pischel, Richard M Ransohoff, Hans-peter HartungAbstract:Abstract Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-γ-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced Experimental Autoimmune Neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1α and MIP-1β were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.
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Expression of integrins in Experimental Autoimmune Neuritis and guillain‐barré syndrome
Annals of Neurology, 1998Co-Authors: Stefano C. Previtali, Juan J. Archelos, Hans-peter HartungAbstract:: Integrins are a subclass of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Integrins influence transendothelial migration of lymphocytes and monocytes and are suitable targets for Experimental immunotherapy. They are critically involved in the pathogenesis of Autoimmune Neuritis and abnormally expressed in human neuropathies. Also, the role of integrins in myelination, neurite outgrowth, and nerve regeneration suggests that they could be involved in the recovery phase of immune-mediated neuropathies. We investigated by immunohistochemistry the expression of a number of integrin subunits during the course of Experimental Autoimmune Neuritis (EAN). Results were compared with the human immune neuropathy Guillain-Barre syndrome (GBS) and extended in vitro. Inflammation and demyelination in both EAN and GBS induced the down-regulation of beta4 integrin in Schwann cells (SCs), whereas loss of alpha2 was noted only in EAN. When axonal loss was present, SCs displayed alpha5 integrin, in both EAN and GBS. In vitro, basal lamina and inflammatory cytokines modulated the expression of beta4 in SCs, but they did not influence alpha2 and alpha5 expression. Finally, integrins were differentially expressed in blood vessels during EAN. In conclusion, the spatiotemporal changes in integrin expression may be used to characterize, stage, and better understand the pathogenesis and evolution of inflammation during GBS and EAN. This may help to establish useful, novel therapy for immune-mediated neuropathies.
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Attenuation of Experimental Autoimmune Neuritis in the Lewis rat by treatment with an antibody to L-selectin
Neuroscience Letters, 1997Co-Authors: Juan J. Archelos, T Fortwängler, Hans-peter HartungAbstract:Abstract The leukocyte adhesion molecule L -selectin plays a key role in the initial steps of transendothelial migration of T cells and monocytes. In this study we investigated the role of L -selectin in the pathogenesis of Experimental Autoimmune Neuritis (EAN) an animal model of the Guillain–Barre syndrome. EAN was induced in Lewis rats by sensitization with peripheral nerve myelin. Treatment with HRL3, a monoclonal antibody to L -selectin, efficiently suppressed clinical signs of EAN. Histological examination of the peripheral nervous system (PNS) revealed a marked reduction of inflammatory infiltrates and demyelination during treatment with HRL3. We conclude that L -selectin-dependent mechanisms are of pathophysiological relevance in EAN. Modulation of L -selectin in vivo could be a novel therapeutic approach to Autoimmune diseases of the PNS.
