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" לקראת טיפול תאי לשלב המתקדם של מחלת טרשת נפוצה "
Nishri, Yossi
Ben-Hur, Tamir
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Latin Dissertation
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| Language of Document
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English
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| Record Number
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1112328
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| Doc. No
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TLpq2526129294
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| Main Entry
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Ben-Hur, Tamir
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Nishri, Yossi
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| Title & Author
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לקראת טיפול תאי לשלב המתקדם של מחלת טרשת נפוצה\ Nishri, YossiBen-Hur, Tamir
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| College
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The Hebrew University of Jerusalem (Israel)
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| Date
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2019
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| student score
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2019
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| Degree
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Ph.D.
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| Page No
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105
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| Abstract
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Multiple sclerosis (MS) is the most common cause of acquired neurological disability in young adults. It is a multifocal disease defined histologically by multiple inflammatory lesions of demyelination, axonal injury, astrogliosis and varying degrees of remyelination. MS has two clinical phases reflecting distinct but interrelated pathological processes: (1) a systemic (auto-) immune-mediated relapsing-remitting (RR) phase manifesting with episodes of focal inflammation and demyelination, and (2) a secondary chronic progressive (CP) phase in which systemic auto-immunity declines, and the disease instead manifests with compartmentalized central nervous system (CNS)-driven inflammatory demyelination and neurodegeneration. In contrast to the increasing number of effective immunomodulatory disease modifying treatments (DMTs) for RR disease, currently, there are no therapies for the progressive stage of the disease, except for the recently approved monoclonal drug Ocrelizumab, that provides only mild benefit. The progressive stage represents therefore a major unmet clinical need. One of the main obstacles for development of treatments is the lack of clinically relevant animal models for CP-MS, which is a necessary prerequisite for drug development. Ideally, such a model would represent the heterogeneous chronic active and inactive inflammatory lesions of demyelination, remyelination and neurodegeneration, which are closely associated with progressive clinical disability. This pathological process progresses in spite of diminished systemic activity of autoimmunity against the CNS myelin. Clearly, all existing MS models, including acute toxic-induced focal demyelination, viral models and even most experimental autoimmune encephalomyelitis (EAE) models have significant drawbacks that limit their use as CP-MS models. Recent developments in stem cell biology have demonstrated the potential for treating CNS myelin damage by stem cell transplantation. The basic rationale of regenerative cell therapy is replacement of lost endogenous oligodendrocytes by exogenously transplanted cells. Moreover, the potent therapeutic properties of stem cells, namely immunomodulation, neurotrophic support and neuroprotection enable combination of the rationale of cell replacement with modulation of the toxic disease environment and support for endogenous repair. The therapeutic properties of neuroglial stem/progenitor cells and their delivery to the site of the disease make cell therapy a promising candidate for treating the CNS compartmentalized disease in chronic progressive MS. The challenges of cell therapy in real life will include survival in the host (hostile) CNS environment, long-range migration, and overcoming multiple environmental impediments for remyelination. In addition, the optimal cellular platform and its developmental stage for remyelination (with combined immunomodulatory and neurotrophic properties) are not known at this time. Furthermore, it is not clear whether oligodendrocyte progenitor cells (OPCs), the main CNS remyelinating cell, exhibit immunomodulation, neurotrophic and neuroprotection properties and whether cell transplantation induces ongoing therapeutic effects in clinically-relevant models of chronic/relapsing-progressive MS. In order to address these questions, in the first part of my work I explored the EAE model in Biozzi antibody high (ABH) mice, a suggested model for CP-MS. To enable better understanding of the model and to assess its relevance as an experimental tool for studying human MS, I characterized clinical and immunopathological parameters of the model and compared the data to human MS. Mice exhibited clinical progression from a uniform relapsing phase to a variable, secondary, progressive phase of the disease. This was accompanied by development of spinal demyelinated plaques with variable degrees of axonal loss, which exhibited initial high inflammatory activity, followed by appearance of inactive lesions. There was blood-brain barrier (BBB) breakdown during relapses and partial closure in the late chronic phase. Demyelinated lesions developed in close association with local meningeal immune cell infiltrates that acquired typical features of tertiary lymphoid organs (TLO) in the late chronic phase. Immune cell characterization showed a transition from a T cell mediated disease during relapses to combined B and T cell mediated disease in the late chronic phase of EAE.
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Antibodies
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Disease
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Magnetic resonance imaging
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Multiple sclerosis
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Neurodegeneration
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Vitamin deficiency
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