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Ralf Gold - One of the best experts on this subject based on the ideXlab platform.
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induction of regulatory properties in the intestinal immune system by dimethyl fumaRate in Lewis Rat experimental autoimmune neuritis
Frontiers in Immunology, 2019Co-Authors: Kalliopi Pitarokoili, Hussein Bachir, Melissa Sgodzai, Thomas Gruter, Steffen Haupeltshofer, Alexander Duscha, Xiomara Pedreiturria, Jeremias Motte, Ralf GoldAbstract:Objective: Dimethyl fumaRate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EΑΝ) in the Lewis Rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Methods: Lewis Rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria and Peyer patches) in duodenum, jejunum and ileum were performed ex vivo. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. Results: In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4+ CD25+ regulatory T cells were increased in the Peyer patches. In vivo, the protective effect of these regulatory cells was verified by cell transfer into recipient EAN Rats. Conclusions: Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.
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Lewis Rat model of experimental autoimmune encephalomyelitis
Current protocols in protein science, 2017Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Ralf GoldAbstract:In this unit, we describe in detail the most common methods used to break immunological tolerance for central myelin antigens and induce experimental autoimmune encephalomyelitis (EAE) in Lewis Rats as an animal model of multiple sclerosis. The resulting disease course ranges from an acute monophasic disease to a chronic relapsing or chronic progressive course, which strongly resembles the human disease. These models enable the study of cellular and humoral autoimmunity against major antigenic epitopes of the myelin basic protein, myelin oligodendrocyte glycoprotein, or proteolipid protein. We provide an overview of common immunization protocols for induction of active and passive EAE, assessment and analysis of clinical score, prepaRation and purification of myelin basic protein, and derivation of neuroantigen-specific Rat T cell lines. Finally, we describe the major clinical characteristics of these models. © 2017 by John Wiley & Sons, Inc.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:BACKGROUND Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system. METHODS AND FINDINGS Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN. CONCLUSIONS We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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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, Liat Hayardeny Nisimov, Michael R Hayden, 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.
Mark C Chappell - One of the best experts on this subject based on the ideXlab platform.
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amelioRation of renal injury and oxidative stress by the nnos inhibitor l vnio in the salt sensitive mren2 Lewis congenic Rat
Journal of Cardiovascular Pharmacology, 2012Co-Authors: Liliya M Yamaleyeva, Patricia E Gallagher, Sarah H Lindsey, Jasmina Varagic, Lili Zhang, Alex F Chen, Mark C ChappellAbstract:Salt-sensitivity is a key risk factor for cardiovascular disease and renal injury. AlteRations in renal nitric oxide may contribute to salt-dependent increases in blood pressure and tissue damage. Therefore, we assessed the expression of nitric oxide synthase (NOS) isoforms in the kidney, as well as the effects of nNOS inhibition on renal injury, inflammation and oxidative stress in the female mRen2.Lewis Rat (mRen), a model of salt-sensitive hypertension. We find that a high salt diet (HS, 4% sodium) significantly reduced endothelial NOS mRNA (2.6 fold) and protein (1.5 fold) but increased nNOS mRNA (2.4 fold) and protein (1.9 fold) in the renal cortex of these animals. Immunostaining for nNOS also appeared higher in macula densa and cortical tubules of the HS Rats. Circulating nitRate and nitrite levels were reduced, as well as the tissue levels of the NOS co-factor tetrahydrobiopterin (BH4). Cortical markers of oxidative stress (4HNE, 8-OH-deoxyguanosine) and fibrosis were increased; however, mRNA levels of the NAD(P)H oxidase components NOX4, p22phox and p47phox were reduced. Chronic treatment with the nNOS inhibitor L-VNIO did not influence SBP after 4 weeks but significantly attenuated albuminuria, renal fibrosis, inflammation and indices of oxidative stress. We conclude that an increase in nNOS expression in conjunction with reduced levels of cortical BH4 may stimulate oxidative stress and renal injury in the salt-sensitive female mRen2.Lewis Rat.
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progressive diastolic dysfunction in the female mren 2 Lewis Rat influence of salt and ovarian hormones
Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2008Co-Authors: Leanne Groban, Liliya M Yamaleyeva, Brian M Westwood, Timothy T Houle, Marina Lin, Dalane W Kitzman, Mark C ChappellAbstract:This study determined the contribution of chronic salt loading and early loss of ovarian hormones on diastolic function in the hypertensive female mRen(2). Lewis Rat, a monogenetic strain that expresses the mouse renin-2 gene in various tissues. Estrogen-intact mRen2 Rats fed a high salt (HS) (8% sodium chloride) diet exhibited early diastolic dysfunction when compared to normal salt-fed (NS) (1% sodium chloride) Rats. In contrast, ovariectomized (OVX) Rats on either NS or HS diets showed impaired relaxation with evidence of elevated left ventricular filling pressures (E/e') or pseudonormalization. This more advanced stage of diastolic dysfunction was associated with increases in interstitial cardiac fibrosis and high circulating levels of aldosterone, two factors leading to reduced ventricular compliance. These findings may explain the preponderance of diastolic dysfunction and diastolic heart failure in postmenopausal women and provide a potential animal model for evaluating prevention and treatment interventions for this disorder.
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estrogen and salt sensitivity in the female mren 2 Lewis Rat
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2006Co-Authors: Mark C Chappell, Liliya M Yamaleyeva, Brian M WestwoodAbstract:The present study determined whether early loss of estrogen influences salt-sensitive changes in blood pressure, renal injury, and cardiac hypertrophy as well as the effects on the circulating reni...
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differential expression of nuclear at1 receptors and angiotensin ii within the kidney of the male congenic mren2 Lewis Rat
American Journal of Physiology-renal Physiology, 2006Co-Authors: Karl D Pendergrass, David B Averill, Carlos M Ferrario, Debra I Diz, Mark C ChappellAbstract:We established a new congenic model of hypertension, the mRen2.Lewis Rat and assessed the intracellular expression of angiotensin peptides and receptors in the kidney. The congenic strain was estab...
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estrogen or the at1 antagonist olmesartan reverses the development of profound hypertension in the congenic mren2 Lewis Rat
Hypertension, 2003Co-Authors: Mark C Chappell, David B Averill, Carlos M Ferrario, Patricia E Gallagher, Bridget K BrosnihanAbstract:The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2).Lewis Rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2).Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2).Lewis (OVX) systolic blood pressure averaged 195±3.7 mm Hg versus 141±4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentRation, as well as urinary excretion of Ang II, 8-isoprostane F 2α , and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125±2.9 mm Hg, n=7, P 1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113±5.4 mm Hg (n=6, P
Kalliopi Pitarokoili - One of the best experts on this subject based on the ideXlab platform.
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induction of regulatory properties in the intestinal immune system by dimethyl fumaRate in Lewis Rat experimental autoimmune neuritis
Frontiers in Immunology, 2019Co-Authors: Kalliopi Pitarokoili, Hussein Bachir, Melissa Sgodzai, Thomas Gruter, Steffen Haupeltshofer, Alexander Duscha, Xiomara Pedreiturria, Jeremias Motte, Ralf GoldAbstract:Objective: Dimethyl fumaRate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EΑΝ) in the Lewis Rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Methods: Lewis Rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria and Peyer patches) in duodenum, jejunum and ileum were performed ex vivo. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. Results: In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4+ CD25+ regulatory T cells were increased in the Peyer patches. In vivo, the protective effect of these regulatory cells was verified by cell transfer into recipient EAN Rats. Conclusions: Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.
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Lewis Rat model of experimental autoimmune encephalomyelitis
Current protocols in protein science, 2017Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Ralf GoldAbstract:In this unit, we describe in detail the most common methods used to break immunological tolerance for central myelin antigens and induce experimental autoimmune encephalomyelitis (EAE) in Lewis Rats as an animal model of multiple sclerosis. The resulting disease course ranges from an acute monophasic disease to a chronic relapsing or chronic progressive course, which strongly resembles the human disease. These models enable the study of cellular and humoral autoimmunity against major antigenic epitopes of the myelin basic protein, myelin oligodendrocyte glycoprotein, or proteolipid protein. We provide an overview of common immunization protocols for induction of active and passive EAE, assessment and analysis of clinical score, prepaRation and purification of myelin basic protein, and derivation of neuroantigen-specific Rat T cell lines. Finally, we describe the major clinical characteristics of these models. © 2017 by John Wiley & Sons, Inc.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:BACKGROUND Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system. METHODS AND FINDINGS Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN. CONCLUSIONS We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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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, Liat Hayardeny Nisimov, Michael R Hayden, 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.
Bjorn Ambrosius - One of the best experts on this subject based on the ideXlab platform.
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Lewis Rat model of experimental autoimmune encephalomyelitis
Current protocols in protein science, 2017Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Ralf GoldAbstract:In this unit, we describe in detail the most common methods used to break immunological tolerance for central myelin antigens and induce experimental autoimmune encephalomyelitis (EAE) in Lewis Rats as an animal model of multiple sclerosis. The resulting disease course ranges from an acute monophasic disease to a chronic relapsing or chronic progressive course, which strongly resembles the human disease. These models enable the study of cellular and humoral autoimmunity against major antigenic epitopes of the myelin basic protein, myelin oligodendrocyte glycoprotein, or proteolipid protein. We provide an overview of common immunization protocols for induction of active and passive EAE, assessment and analysis of clinical score, prepaRation and purification of myelin basic protein, and derivation of neuroantigen-specific Rat T cell lines. Finally, we describe the major clinical characteristics of these models. © 2017 by John Wiley & Sons, Inc.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:BACKGROUND Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system. METHODS AND FINDINGS Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN. CONCLUSIONS We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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dimethyl fumaRate amelioRates Lewis Rat experimental autoimmune neuritis and mediates axonal protection
PLOS ONE, 2015Co-Authors: Kalliopi Pitarokoili, Bjorn Ambrosius, Lisa Schrewe, Daniela Meyer, Ralf GoldAbstract:Dimethyl fumaRate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis Rat to study the effects of dimethyl fumaRate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumaRate given at 45 mg/kg twice daily by oral gavage significantly amelioRated clinical neuritis by reducing demyelination and axonal degeneRation in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltRates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneRation through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumaRate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumaRate may represent an innovative therapeutic option in human autoimmune neuropathies.
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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, Liat Hayardeny Nisimov, Michael R Hayden, 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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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.
Hans Link - One of the best experts on this subject based on the ideXlab platform.
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administRation of encephalitogenic MBP peptides: synergistic effects of MBP 68–86 and 87–99
2015Co-Authors: Jin-qing Liu, Bao-guo Xiao, Xue-feng Bai, Fu-dong Shi, Michael Levi, Maha Mustafa, Britta Wahren, Hans LinkAbstract:route Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis Rat by immunization with myelin basic protein (MBP) and Freund’s adjuvant (CFA) is mediated by CD4F T cells specific for the MBP amino acid sequences 68–86 and 87–99. To further define the principles of nasal tolerance induction, we geneRated three different MBP peptides (MBP 68–86, 87–99 and the non-encephalitogenic peptide 110–128), and evaluated whether their nasal administRation on day –11, –10, –9, –8 and –7 prior to immunization with guinea pig MBP (gp-MBP) F CFA confers protection to Lewis Rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68–86 and 87–99, MBP 68–86 being more potent, but not with MBP 110–128. Neither MBP 68–86 nor 87–99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administRation of a mixture of MBP 68–86 and 87–99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rat
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laquinimod abr 215062 suppresses the development of experimental autoimmune encephalomyelitis modulates the th1 th2 balance and induces the th3 cytokine tgf β in Lewis Rats
Journal of Neuroimmunology, 2004Co-Authors: Jian-she Yang, Bao-guo Xiao, Gunnar Hedlund, Hans LinkAbstract:Abstract The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis Rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4 + T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of T H 2/T H 3 cytokines IL-4, IL-10 and TGF-β. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
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laquinimod abr 215062 suppresses the development of experimental autoimmune encephalomyelitis modulates the th1 th2 balance and induces the th3 cytokine tgf β in Lewis Rats
Journal of Neuroimmunology, 2004Co-Authors: Jian-she Yang, Bao-guo Xiao, Gunnar Hedlund, Hans LinkAbstract:The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis Rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4+ T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of TH2/TH3 cytokines IL-4, IL-10 and TGF-beta. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.