Cell Therapy In Multiple Sclerosis Research Articles

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab

A backpack-based myeloid cell therapy for multiple sclerosis

Multiple sclerosis (MS) is an incurable autoimmune disease and is currently treated by systemic immunosuppressants with off-target side effects. Although aberrant myeloid function is often observed in MS plaques in the central nervous system (CNS), the role of myeloid cells in therapeutic intervention is currently overlooked. Here, we developed a myeloid cell-based strategy to reduce the disease burden in experimental autoimmune encephalomyelitis (EAE), a mouse model of progressive MS. We developed monocyte-adhered microparticles ("backpacks") for activating myeloid cell phenotype to an anti-inflammatory state through localized interleukin-4 and dexamethasone signals. We demonstrate that backpack-laden monocytes infiltrated into the inflamed CNS and modulated both the local and systemic immune responses. Within the CNS, backpack-carrying monocytes regulated both the infiltrating and tissue-resident myeloid cell compartments in the spinal cord for functions related to antigen presentation and reactive species production. Treatment with backpack-monocytes also decreased the level of systemic pro-inflammatory cytokines. Additionally, backpack-laden monocytes induced modulatory effects on TH1 and TH17 populations in the spinal cord and blood, demonstrating cross talk between the myeloid and lymphoid arms of disease. Backpack-carrying monocytes conferred therapeutic benefit in EAE mice, as quantified by improved motor function. The use of backpack-laden monocytes offers an antigen-free, biomaterial-based approach to precisely tune cell phenotype invivo, demonstrating the utility of myeloid cells as a therapeutic modality and target.

Treatment of EAE mice with Treg, G-MDSCand IL-2: a new insight into cell therapy for multiple sclerosis.

Background: This study investigates the therapeutic and protective effects of Tregs, myeloid-derived suppressor cells (MDSCs) and IL-2 on multiple sclerosis (MS) disease model. Materials & methods: C57BL/6 mice were immunized to develop an experimental autoimmune encephalomyelitis (EAE) model. We then investigated effects of pre- and post-treatment EAE mice with Tregs, MDSCs and IL-2 on inflammation and demyelination in brain tissue, and on the number of Treg, granulocytic-MDSC and Th-17 cells in spleen. Results: Pre- and post-treatment of EAE mice by Tregs, MDSCs and IL-2 resulted in no weight change, reduced Th-17 cells and suppression of pathological properties. Conclusion: Pre- and post-treatment of immunized mice by Tregs, MDSCs and IL-2 prevent EAE induction.

Neurophysiological outcomes following mesenchymal stem cell therapy in multiple sclerosis

ObjectiveTo report on neurophysiological outcomes derived from transcranial magnetic stimulation (TMS) following autologous mesenchymal stem cells (aMSCs) therapy in patients with multiple sclerosis (MS). Methods20 adults with confirmed MS were recruited to participate in a phase II randomized control trial to assess the safety and potential benefits of aMSCs infusion. At Week 0, patients were randomly assigned to receive either aMSCs (n = 9) or a placebo infusion (n = 11). At Week 24, the placebo group received the aMSCs infusion. Blind assessments were performed at Weeks 0, 24 and 48. Outcomes consisted of TMS measures of corticomotor excitability and motor conduction along with measures of motor impairments and disability. ResultsPost-infusion, no change was detected in measures of corticomotor excitability or measures of intra- or interhemispheric inhibition. The latency of motor evoked potentials and central motor conduction time were significantly prolonged. These changes in motor conduction were associated with declines in hand dexterity post-infusion. ConclusionClinical and neurophysiological measures showed no improvement following aMSCs therapy in this cohort of MS patients. SignificanceAlthough promising, stem cell therapy remains elusive regarding its benefits in influencing disease activity in MS patients.

Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein-Barr Virus-Specific T Cell Therapy.

Background: Increasing evidence indicates a role for Epstein–Barr virus (EBV) in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity. We have previously reported results of a phase I clinical trial of autologous EBV-specific T cell therapy in MS 6 months after treatment.Objective: To investigate longer-term outcomes in MS patients who received autologous EBV-specific T cell therapy.Methods: We assessed participants 2 and 3 years after completion of T cell therapy.Results: We collected data from all 10 treated participants at year 2 and from 9 participants at year 3. No serious treatment-related adverse events were observed. Four participants had at least some sustained clinical improvement at year 2, including reduced fatigue in three participants, and reduced Expanded Disability Status Scale score in two participants. Three participants experienced a sustained improvement in at least some symptoms at year 3. More sustained improvement was associated with higher EBV-specific CD8+ T cell reactivity in the administered T cell product.Conclusion: Autologous EBV-specific T cell therapy is well-tolerated, and some degree of clinical improvement can be sustained for up to 3 years after treatment.

Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation.

Purpose of reviewIn this review, we summarize the recently published literature that demonstrates the efficacy and safety of autologous haematopoietic stem cell therapy (AHSCT) in multiple sclerosis (MS) and highlight the importance of supportive care required for the safe and well-tolerated delivery of AHSCT.Recent findingsMS is an autoimmune inflammatory and degenerative disorder of the central nervous system (CNS). In the majority of patients, the illness runs a relapsing remitting course (RRMS), culminating in a secondary progressive phase with gradual accumulation of fixed disabilities. Currently available disease-modifying therapies suppress CNS inflammation but have a limited effect on preventing disease progression for which there remains no effective therapy. Over the last two decades, there has been increasing evidence that AHSCT is a highly effective therapeutic strategy for treatment-resistant inflammatory types of MS, especially RRMS. Concerns about the safety of AHSCT in MS, usually a nonlife-threatening disease, have previously limited its use. However, AHSCT can now be delivered safely with major long-term benefits because of increasing transplant centre experience, judicious patient selection and good supportive care.SummaryMS is currently the fastest growing indication for AHSCT in Europe. Supportive care before, during and after the transplant period is key to the successful delivery of AHSCT.

Stem cell therapy for multiple sclerosis

Stem cell therapy for multiple sclerosis

Stem cell therapy for multiple sclerosis

Stem cell therapy for multiple sclerosis

No Evidence of Disease Activity after Five Years of Autologous Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Detailed Report of Five Patients

No Evidence of Disease Activity after Five Years of Autologous Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Detailed Report of Five Patients

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.

A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells.

Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.

Stem Cell Therapy for Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS). It is characterized by demyelination and neuronal loss that is induced by attack of autoreactive T cells to the myelin sheath and endogenous remyelination failure, eventually leading to functional neurological disability. Although recent evidence suggests that MS relapses are induced by environmental and exogenous triggers such as viral infections in a genetic background, its very complex pathogenesis is not completely understood. Therefore, the efficiency of current immunosuppression-based therapies of MS is too low, and emerging disease-modifying immunomodulatory agents such as fingolimod and dimethyl fumarate cannot stop progressive neurodegenerative process. Thus, the cell replacement therapy approach that aims to overcome neuronal cell loss and remyelination failure and to increase endogenous myelin repair capacity is considered as an alternative treatment option. A wide variety of preclinical studies, using experimental autoimmune encephalomyelitis model of MS, have recently shown that grafted cells with different origins including mesenchymal stem cells (MSCs), neural precursor and stem cells, and induced-pluripotent stem cells have the ability to repair CNS lesions and to recover functional neurological deficits. The results of ongoing autologous hematopoietic stem cell therapy studies, with the advantage of peripheral administration to the patients, have suggested that cell replacement therapy is also a feasible option for immunomodulatory treatment of MS. In this chapter, we overview cell sources and applications of the stem cell therapy for treatment of MS. We also discuss challenges including those associated with administration route, immune responses to grafted cells, integration of these cells to existing neural circuits, and risk of tumor growth. Finally, future prospects of stem cell therapy for MS are addressed.

Cell Therapy for Multiple Sclerosis.

Cell therapy is considered a promising potential treatment for multiple sclerosis, perhaps particularly for the progressive form of the disease for which there are currently no useful treatments. Over the past two decades or more, much progress has been made in understanding the biology of MS and in the experimental development of cell therapy for this disease. Three quite distinct forms of cell therapy are currently being pursued. The first seeks to use stem cells to replace damaged myelin-forming oligodendrocytes within the CNS; the second aims, in effect, to replace the individual's misfunctioning immune system, making use of haematopoietic stem cells; and the third seeks to utilise endogenous stem cell populations by mobilisation with or without in vitro expansion, exploiting their various reparative and neuroprotective properties. In this article we review progress in these three separate areas, summarising the experimental background and clinical progress thus far made.

The role of stem cell therapy in multiple sclerosis: An overview of the current status of the clinical studies.

The complexity of multiple sclerosis (MS) and the incompetence of a large number of promised treatments for MS urge us to plan new and more effective therapeutic approaches that aim to suppress ongoing autoimmune responses and induction of local endogenous regeneration. Emerging data propose that hematopoietic, mesenchymal, and neural stem cells have the potential to restore self-tolerance, provide in situ immunomodulation and neuroprotection, as well as promote regeneration. Thus, in this article, we will first provide an overview of the cell sources for proposed mechanisms that contribute to the beneficial effects of stem cell transplantation, the ideal route and/or timing of stem cell-based therapies for each main stem cell group, and finally, an overview of the current status of stem cell research in clinical trial stages in MS by comparable and healthy therapeutic effects of different stem cell therapies for MS patients.

Cell therapy for multiple sclerosis: a new hope

Multiple sclerosis is a chronic demyelinating autoimmune disease with uncertain aetiology. Due to the heterogeneity of the disease, patients may present with a wide variety of neurological symptoms such as optic neuritis, sensory deficits or cerebel lar dysfunction. It remains a disease showing little hope in terms of finding a cure. Although current therapies, such as interferon-β and glatiramer acetate, provide symptomatic relief and can delay the degenerative process, there is still a large impact on quality of life as these therapies lack an ability to reverse damage occurring prior to treatment. Recently, cell therapy has emerged as a promising treatment with signs of recovery both pathologically and clinically in a variety of animal models. Given the multifaceted capabilities of the various stem cells, including immunomodulation and neuroprotection, their potential use as a comprehensive therapy is much more promising than any pharmacological therapy to date. Here, the latest advances of cell therapy are discussed, in terms of potential efficacy, the various cell types that are used, their mecha nisms of action and the obstacles that still need to be overcome for translation into a clinical setting.

P031 - Mesenchymal stem cell therapy in multiple sclerosis: An updated review of the current clinical trials

Introduction Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS). The complexity of (MS) and the incompetence of a large number of promise treatments in MS urge us to plan new and more effective therapeutic approaches that aim to suppress ongoing autoimmune responses and induction of local endogenous regeneration. Stem cells (SCs) have uncovered a new view as a therapeutic tool in neurological disorders such as MS. These cells are pluripotent cells with the capacity to give rise to different cell types. There are two main stem cell types, embryonic stem cells (ESs) and adult stem cells. In adults, stem cells include hematopoietic stem cells, mesenchymal stem cells (MSCs) and neural stem cells. MSCs are self-replicating cells which can play a role in differentiating in multidirectional pathways, such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon–ligament fibroblasts, adipocytes and neural cells. Methods We studied recent (2007–2014) clinical trials and review articles of stem cell therapy for multiple sclerosis to achieve the best adult stem cell type and the most effective and safest route in order of managing them. In this article we will first provide an overview of the cell sources for, proposed mechanisms that contribute to the beneficial effects of stem cell transplantation and the ideal route and/or timing of stem cell-based therapies for MSC. Results Seven clinical trials were found (Table 1 ). In some studies we detect critical adverse events that has been indicated some types of SCs act as carcinogen factors. According to our research, the best stem cell to transfer MS patients was mesenchymal stem cells and injecting intravenously is the best way to administrate. By this goals we prevent from meningeal irritation that will happen in intrathecally administration. Conclusion Overall, we recommend intravenous MSCs as the best kind of stem cell therapy for autoimmune disorders like MS. It is clear that more studies should be done to prove efficacy and safety of these therapeutic approaches. Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS). The complexity of (MS) and the incompetence of a large number of promise treatments in MS urge us to plan new and more effective therapeutic approaches that aim to suppress ongoing autoimmune responses and induction of local endogenous regeneration. Stem cells (SCs) have uncovered a new view as a therapeutic tool in neurological disorders such as MS. These cells are pluripotent cells with the capacity to give rise to different cell types. There are two main stem cell types, embryonic stem cells (ESs) and adult stem cells. In adults, stem cells include hematopoietic stem cells, mesenchymal stem cells (MSCs) and neural stem cells. MSCs are self-replicating cells which can play a role in differentiating in multidirectional pathways, such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon–ligament fibroblasts, adipocytes and neural cells. We studied recent (2007–2014) clinical trials and review articles of stem cell therapy for multiple sclerosis to achieve the best adult stem cell type and the most effective and safest route in order of managing them. In this article we will first provide an overview of the cell sources for, proposed mechanisms that contribute to the beneficial effects of stem cell transplantation and the ideal route and/or timing of stem cell-based therapies for MSC. Seven clinical trials were found (Table 1 ). In some studies we detect critical adverse events that has been indicated some types of SCs act as carcinogen factors. According to our research, the best stem cell to transfer MS patients was mesenchymal stem cells and injecting intravenously is the best way to administrate. By this goals we prevent from meningeal irritation that will happen in intrathecally administration. Overall, we recommend intravenous MSCs as the best kind of stem cell therapy for autoimmune disorders like MS. It is clear that more studies should be done to prove efficacy and safety of these therapeutic approaches.

Is intra-muscular transplantation of human placental stromal cells a feasible approach for cell therapy in Multiple Sclerosis?

A key issue in developing indirect cell based therapy for Multiple Sclerosis (MS) is determining the optimal route of cell delivery. Isolated and expanded human placental stromal cells (hPSC) represent a leading candidate for an off-the-shelf cell product with powerful immunomodulatory properties for allogeneic transplantation. We examined whether multiple intramuscular hPSC delivery is a feasible approach to treat neuroinflammatory diseases in a mouse model. Specifically, we examined both the fate of the implanted hPSC and their effect in experimental autoimmune encephaloemyelitis (EAE) model induced with MOG peptide.

Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain.

ObjectiveThe mechanism of action of anti-B cell therapy in multiple sclerosis (MS) is not fully understood. Here, we compared the effect of anti-CD20 therapy on microglial activation in two distinct focal rat models of MS.MethodsThe effect of anti-CD20 therapy on lesion formation and extralesional microglial activation was evaluated in the fDTH-EAE (experimental allergic encephalomyelitis) model, which is a focal demyelinating type-IV delayed-type hypersensitivity lesion. For comparison, effects were also assessed in the focal humoral MOG model induced by intracerebral injection of cytokine in myelin oligodendrocyte glycoprotein immunized rats. Microglial activation was assessed in situ and in vivo using the TSPO SPECT ligand [125I]DPA-713, and by immunostaining for MHCII. The effect of treatment on demyelination and lymphocyte recruitment to the brain were evaluated.ResultsAnti-CD20 therapy reduced microglial activation, and lesion formation in the humoral model, but it was most effective in the antibody-independent fDTH-EAE. Immunohistochemistry for MHCII also demonstrated a reduced volume of microglial activation in the brains of anti-CD20-treated fDTH-EAE animals, which was accompanied by a reduction in T-cell recruitment and demyelination. The effect anti-CD20 therapy in the latter model was similarly strong as compared to the T-cell targeting MS compound FTY720.InterpretationThe suppression of lesion development by anti-CD20 treatment in an antibody-independent model suggests that B-cells play an important role in lesion development, independent of auto-antibody production. Thus, CD20-positive B-cell depletion has the potential to be effective in a wider population of individuals with MS than might have been predicted from our knowledge of the underlying histopathology.

The Role of Stem Cell Therapy in Multiple Sclerosis: an Overview of the Current Status of the Clinical Studies

The complexity of multiple sclerosis (MS) and the incompetence of a large number of promise treatments in MS urge us to plan new and more effective therapeutic approaches that aim to suppress ongoing autoimmune responses and induction of local endogenous regeneration. Emerging data propose that hematopoietic, mesenchymal and neural stem cells have the potential to restore self-tolerance, to provide in situ immunomodulation and neuroprotection as well as to promote regeneration. Thus in this article we will first provide an overview of the cell sources for, proposed mechanisms that contribute to the beneficial effects of stem cell transplantation and the ideal route and/or timing of stem cell-based therapies for each main stem cell group. Finally, we provide an overview of the current status of stem cell researches in clinical trial stages in MS by comparable and healthy therapeutic effects of different stem cells therapy in MS patients. Keywords: Cell therapy and transplantation, Hematopoietic stem cells, Mesenchymal stem cells, Neural stem/precursor cells, Stem cells.

Intrathecal Mesenchymal Stem Cell Therapy in Multiple Sclerosis: A Follow-Up Study for Five Years After Injection

Background: Mesenchymal stem cell therapy has been used in multiple sclerosis (MS) in order to modulate the course of the disease in previous studies. One of the major concerns in such cases is long term safety or efficacy of this type of therapy. Objectives: This study was conducted to report the clinical status of five patients with secondary progressive multiple sclerosis and one patient with neuromyelitis optica, five years after an autologous intrathecal mesenchymal stem cell (MSC) injection. Patients and Methods: The patients (three male, three female) had a progressive course nonresponsive to the conventional immunomodulatory treatments with Expanded Disability Status Scale (EDSS) score of 3.5 to 6. They received the MCSs after discontinuing other treatments. They were examined annually to assess the disease activity and possible complications. Results: Two patients had no change in their EDSS scores. One was diagnosed to have Devic’s disease decreased one score in the EDSS, but experienced four relapses during these five years. Three patients had an increase in EDSS scores by 1-2 scores after five years. Two experienced relapses after injection. There was no significant adverse reaction, infection, or neoplasm during this period of follow up. Conclusions: Intrathecal mesenchymal stem cell therapy for MS is generally safe and did not result in any adverse reaction like malignancy for a relatively long period of time. At least half of the patients had no change in their EDSS and the remaining patients had a delay in disease progress.