Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory v...Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.展开更多
A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)wi...A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)with a good tolerability and efficacy.1 CAR-T cells rank among the breakthrough therapeutic approaches,transforming the field of cancer and autoimmune conditions including neuroimmunological disorders.B-cell maturation antigen(BCMA)and CD19 antigen are B-cell target antigens frequently used in CAR constructs for autoimmune diseases.1,2 In addition to the B-cell depletion in the peripheral blood,CAR-T cells allow deep depletion of tissue-resident B cells e.g.,in lymphoid tissues and hard-to-reach compartments such as the central nervous system(CNS),an effect that has not been observed with antibody-based B-cell depletion therapies.However,little is known about direct and indirect effects of CAR-T cells on microglia,even though CNS-resident microglial cells are involved as one of the key drivers and maintainers of the compartmentalized neuroinflammation and neurodegeneration during MS progression.This is confirmed by emerging evidence that smoldering neurodegenerative processes are hallmarked by chronic microglia-mediated neuroinflammation with progressive axonal injury,resulting in disability progression independent of relapse activity(PIRA)and brain atrophy.1 To date,none of the available therapies for MS are fully effective at preventing disease progression and PIRA.展开更多
Background Multiple sclerosis （MS） is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantati...Background Multiple sclerosis （MS） is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantation （ASCT） has been introduced in the treatment of refractory forms of multiple sclerosis. In this study, the clinical outcomes followed by ASCT were evaluated for patients with progressive MS. Methods Twenty-two patients with secondary progressive MS were treated with ASCT. Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony stimulating factor. Etoposide, melphalan, carmustin and cytosine arabinoside were administered as conditioning regimen. Outcomes were evaluated by the expanded disability status scale and progression free survival. No maintenance treatment was administered during a median follow-up of 39 months （range, 6 to 59 months）. Results No death occurred following the treatment. The overall confirmed progression free survival rate was 77% up to 59 months after transplantation which was significantly higher compared with pre-transplantation （P=0.000）. Thirteen patients （59%） had remarkable improvement in neurological manifestations, four （18%） stabilized their disability status and five （23%） showed clinical recurrence of active symptoms. Conclusions ASCT as a therapy is safe and available. It can improve or stabilize neurological manifestations in most patients with progressive MS following failure of conventional therapy.展开更多
Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a v...Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.展开更多
Multiple sclerosis(MS)is a neurodegenerative and inflammatory disease usually presenting with acute demyelinating events that can start as,or progress to,chronic damage.The development of animal experimental models,sp...Multiple sclerosis(MS)is a neurodegenerative and inflammatory disease usually presenting with acute demyelinating events that can start as,or progress to,chronic damage.The development of animal experimental models,specific for each stage of MS will aid in the design of new drugs specific for the different forms of the disease.Animal models of experimental autoimmune encephalomyelitis successfully reflect the pathophysiological mechanisms of the early phases of MS.However,few models resemble the features of the progressive forms of MS such as cortical demyelination and meningeal inflammation.Recently,a few auspicious animal models recapitulating many of the characteristics of progressive MS,aimed at a better understanding of the pathology of these forms of the disease,have been developed.In this review,we will summarize the latest developments in animal models reflecting the cortical and meningeal pathological features of progressive MS,as well as their response to drugs specifically targeting these forms.展开更多
文摘Active inflammation in“inactive”progressive multiple sclerosis:Traditionally,the distinction between relapsing-remitting multiple sclerosis and progressive multiple sclerosis(PMS)has been framed as an inflammatory versus degenerative dichotomy.This was based on a broad misconception regarding essentially all neurodegenerative conditions,depicting the degenerative process as passive and immune-independent occurring as a late byproduct of active inflammation in the central nervous system(CNS),which is(solely)systemically driven.
文摘A recent publication by Qin et al.in Cell reported on the first-inhuman application of anti-BCMA chimeric antigen receptor(CAR)-T cell therapy in patients with treatment-refractory progressive multiple sclerosis(MS)with a good tolerability and efficacy.1 CAR-T cells rank among the breakthrough therapeutic approaches,transforming the field of cancer and autoimmune conditions including neuroimmunological disorders.B-cell maturation antigen(BCMA)and CD19 antigen are B-cell target antigens frequently used in CAR constructs for autoimmune diseases.1,2 In addition to the B-cell depletion in the peripheral blood,CAR-T cells allow deep depletion of tissue-resident B cells e.g.,in lymphoid tissues and hard-to-reach compartments such as the central nervous system(CNS),an effect that has not been observed with antibody-based B-cell depletion therapies.However,little is known about direct and indirect effects of CAR-T cells on microglia,even though CNS-resident microglial cells are involved as one of the key drivers and maintainers of the compartmentalized neuroinflammation and neurodegeneration during MS progression.This is confirmed by emerging evidence that smoldering neurodegenerative processes are hallmarked by chronic microglia-mediated neuroinflammation with progressive axonal injury,resulting in disability progression independent of relapse activity(PIRA)and brain atrophy.1 To date,none of the available therapies for MS are fully effective at preventing disease progression and PIRA.
基金This study was supported by the Education Grant for Talented Person in Beijing (No. 2004ID0501823).
文摘Background Multiple sclerosis （MS） is a continuously disabling disease and it is unresponsive to high dose steroid and immunomodulation with disease progression. The autologous haematopoietic stem cell transplantation （ASCT） has been introduced in the treatment of refractory forms of multiple sclerosis. In this study, the clinical outcomes followed by ASCT were evaluated for patients with progressive MS. Methods Twenty-two patients with secondary progressive MS were treated with ASCT. Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony stimulating factor. Etoposide, melphalan, carmustin and cytosine arabinoside were administered as conditioning regimen. Outcomes were evaluated by the expanded disability status scale and progression free survival. No maintenance treatment was administered during a median follow-up of 39 months （range, 6 to 59 months）. Results No death occurred following the treatment. The overall confirmed progression free survival rate was 77% up to 59 months after transplantation which was significantly higher compared with pre-transplantation （P=0.000）. Thirteen patients （59%） had remarkable improvement in neurological manifestations, four （18%） stabilized their disability status and five （23%） showed clinical recurrence of active symptoms. Conclusions ASCT as a therapy is safe and available. It can improve or stabilize neurological manifestations in most patients with progressive MS following failure of conventional therapy.
文摘Multiple Sclerosis（MS） is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.
文摘Multiple sclerosis(MS)is a neurodegenerative and inflammatory disease usually presenting with acute demyelinating events that can start as,or progress to,chronic damage.The development of animal experimental models,specific for each stage of MS will aid in the design of new drugs specific for the different forms of the disease.Animal models of experimental autoimmune encephalomyelitis successfully reflect the pathophysiological mechanisms of the early phases of MS.However,few models resemble the features of the progressive forms of MS such as cortical demyelination and meningeal inflammation.Recently,a few auspicious animal models recapitulating many of the characteristics of progressive MS,aimed at a better understanding of the pathology of these forms of the disease,have been developed.In this review,we will summarize the latest developments in animal models reflecting the cortical and meningeal pathological features of progressive MS,as well as their response to drugs specifically targeting these forms.
