Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acut...Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.展开更多
Lysophospholipids are small,membrane-derived lipids that act through a growing family of G protein-coupled receptors(GPCRs)that account for around 40% of the known lipid GPCRs.They comprise a range of distinct chemica...Lysophospholipids are small,membrane-derived lipids that act through a growing family of G protein-coupled receptors(GPCRs)that account for around 40% of the known lipid GPCRs.They comprise a range of distinct chemical structures and include glycerophospholipids like lysophosphatidic acid(LPA)and sphingoid lipids like sphingosine 1-phosphate(S1P).S1 Phas five cognate GPCRs,four of which mediate the actions of a current medicine used in the treatment of multiple sclerosis(MS):fingolimod(also known as FTY720 or Gilenya),which was approved by the FDA in 2010.Fingolimod has its origins in Chinese medicine as a derivative of fungal natural products.It′s mechanism of action in MS is partly known,through effects on lymphocyte trafficking,however current research has identified direct CNS actions that may represent a particular opportunity area for natural products and their derivatives that can target lysophospholipid receptors.The history of lysophospholipid receptors and fingolimod will be discussed,along with mechanistic aspects of receptor-ligand interactions,particularly those with disease relevance.展开更多
Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyeliti...Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.展开更多
BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analy...BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analysis of animal experiments has concluded that fingolimod could treat stroke in animal models by effectively reducing lymphocyte infiltration.However,no evidence-based efficacy and safety evaluation of fingolimod in stroke patients is currently available.AIM To determine whether fingolimod could promote reduction of infarction lesion or hematoma and improve neurological prognosis in stroke patients.METHODS Data extracted for treatment effect included count of T-lymphocytes with cluster of differentiation 8 expression(CD8^(+)T cells,×106/mL),lesion volume(infarction or hematoma,mL),and modified Barthel indexes.Data extracted for safety was risk ratio(RR).Overall standard mean difference(SMD)with its 95%confidence interval(95%CI)and pooled effect with its 95%CI were calculated with a fixedeffects model.I-square(I^(2))was used to test the heterogeneity.Funnel plot symmetry and Egger's regression were used to evaluate publication bias.RESULTS Four high-quality randomized controlled trials were included.There was a significant difference in CD8^(+)T cell count(I^(2)=0,overall SMD=-3.59,95%CI:-4.37-2.80,P=0.737)and modified Barthel index(I^(2)=0,overall SMD=2.42,95%CI:1.63-3.21,P=0.290)between the fingolimod and control groups.However,there was no significant difference in lesion volume(I^(2)=10.6%,overall SMD=-0.17,95%CI:-0.75-0.42,P=0.917),fever(pooled RR=0.93,95%CI:0.97-2.32,P=0.864),suspected lung infection(pooled RR=0.90,95%CI:0.33-2.43,P=0.876),or any adverse events occurring at least once(pooled RR=0.82,95%CI:0.36-1.87,P=0.995)between the fingolimod and control groups.There was no publication bias.All of the results were stable as revealed by sensitivity analysis.CONCLUSION Fingolimod improves neurological function in stroke patients without promotion of lesion absorption.Taking fingolimod orally(0.5 mg/d,3 consecutive days)is safe except for patients with rare severe adverse events.展开更多
Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involve...Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.展开更多
Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated tha...Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage （ICH）. The results showed that fingolimod decreased the numbers of circulating CD4~ T, CD8~ T, CD19~ B, NK, and NKT cells and they recovered quickly after the drug＇ was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.展开更多
文摘Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.
文摘Lysophospholipids are small,membrane-derived lipids that act through a growing family of G protein-coupled receptors(GPCRs)that account for around 40% of the known lipid GPCRs.They comprise a range of distinct chemical structures and include glycerophospholipids like lysophosphatidic acid(LPA)and sphingoid lipids like sphingosine 1-phosphate(S1P).S1 Phas five cognate GPCRs,four of which mediate the actions of a current medicine used in the treatment of multiple sclerosis(MS):fingolimod(also known as FTY720 or Gilenya),which was approved by the FDA in 2010.Fingolimod has its origins in Chinese medicine as a derivative of fungal natural products.It′s mechanism of action in MS is partly known,through effects on lymphocyte trafficking,however current research has identified direct CNS actions that may represent a particular opportunity area for natural products and their derivatives that can target lysophospholipid receptors.The history of lysophospholipid receptors and fingolimod will be discussed,along with mechanistic aspects of receptor-ligand interactions,particularly those with disease relevance.
文摘Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.
文摘BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor prognosis.The meta-analysis of animal experiments has concluded that fingolimod could treat stroke in animal models by effectively reducing lymphocyte infiltration.However,no evidence-based efficacy and safety evaluation of fingolimod in stroke patients is currently available.AIM To determine whether fingolimod could promote reduction of infarction lesion or hematoma and improve neurological prognosis in stroke patients.METHODS Data extracted for treatment effect included count of T-lymphocytes with cluster of differentiation 8 expression(CD8^(+)T cells,×106/mL),lesion volume(infarction or hematoma,mL),and modified Barthel indexes.Data extracted for safety was risk ratio(RR).Overall standard mean difference(SMD)with its 95%confidence interval(95%CI)and pooled effect with its 95%CI were calculated with a fixedeffects model.I-square(I^(2))was used to test the heterogeneity.Funnel plot symmetry and Egger's regression were used to evaluate publication bias.RESULTS Four high-quality randomized controlled trials were included.There was a significant difference in CD8^(+)T cell count(I^(2)=0,overall SMD=-3.59,95%CI:-4.37-2.80,P=0.737)and modified Barthel index(I^(2)=0,overall SMD=2.42,95%CI:1.63-3.21,P=0.290)between the fingolimod and control groups.However,there was no significant difference in lesion volume(I^(2)=10.6%,overall SMD=-0.17,95%CI:-0.75-0.42,P=0.917),fever(pooled RR=0.93,95%CI:0.97-2.32,P=0.864),suspected lung infection(pooled RR=0.90,95%CI:0.33-2.43,P=0.876),or any adverse events occurring at least once(pooled RR=0.82,95%CI:0.36-1.87,P=0.995)between the fingolimod and control groups.There was no publication bias.All of the results were stable as revealed by sensitivity analysis.CONCLUSION Fingolimod improves neurological function in stroke patients without promotion of lesion absorption.Taking fingolimod orally(0.5 mg/d,3 consecutive days)is safe except for patients with rare severe adverse events.
文摘Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.
基金supported by the National Basic Research Development Program of China (2013CB966900)the National Natural Science Foundation of China (81241144, 81371372)the National Key Clinical Specialty Construction Program of China
文摘Intracerebral hemorrhage （ICH） leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage （ICH）. The results showed that fingolimod decreased the numbers of circulating CD4~ T, CD8~ T, CD19~ B, NK, and NKT cells and they recovered quickly after the drug＇ was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.
