Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by multifocal regions of inflammation and myelin destruction. Typically, MS runs a protracted clinical course lasting over several decades with episodes of exacerbation followed by variable periods of remission. Available evidence indicates that the cause of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g. viral infection. The development of animal models in which the clinical and histologic pathology is similar to that observed in the majority of MS patients is imperative in order to attempt to better understand the underlying pathological mechanisms contributing to MS. Viral models of demyelination are important tools for studying the pathogenesis of disease. Persistent infection of mice with the neurotropic JHM strain of mouse hepatitis virus (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Combined with the fact that an environmental agent such as a virus is considered to be a contributing cause of MS, the MHV system offers an excellent model in which to study both the underlying immunopathological mechanisms that may drive demyelination in MS patients as well as novel therapeutic methods for promoting remyelination. Stem cells offer an exciting new avenue for treatment of many autoimmune diseases including MS. We have previously demonstrated that surgical engraftment of self-derived neural stem cells (NSCs) into MHV- infected mice with established demyelination results in improved motor skills associated with extensive remyelination. In addition, we have data supporting that the improvement in both clinical and histologic disease is the result of the engrafted NSCs. We have now focused our attention on how to prolong the life- span of transplanted stem cells as we believe these cells are critical in improving functional outcome. This is clinically relevant in that if human stem cells are used for treatment of MS or other human demyelinating diseases, it is likely they will be derived from a donor source that is not genetically similar to an MS patient;therefore, these cells will be rejected early following transplantation as they are not """"""""self-derived"""""""". This research proposal will examine clinically-relevant strategies that may be used for improving the survival of transplanted stem cells by dampening immune responses in the recipient host.

Public Health Relevance

Engraftment of syngeneic mouse neural stem cells (NSCs) into mice with established demyelination results in remyelination associated with recovery of motor skills. However, transplantation of allogeneic mouse NSCs results in rapid rejection associated with no remyelination nor clinical recovery. This proposal will define mechanisms associated with immune-mediated rejection of NSCs as well as methods to dampen the immunogenicity of allogeneic NSCs.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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University of California Irvine
Schools of Arts and Sciences
United States
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Mangale, Vrushali; Marro, Brett S; Plaisted, Warren C et al. (2017) Neural precursor cells derived from induced pluripotent stem cells exhibit reduced susceptibility to infection with a neurotropic coronavirus. Virology 511:49-55
Yandamuri, Soumya S; Lane, Thomas E (2016) Imaging Axonal Degeneration and Repair in Preclinical Animal Models of Multiple Sclerosis. Front Immunol 7:189
Blanc, Caroline A; Grist, Jonathan J; Rosen, Hugh et al. (2015) Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. Am J Pathol 185:2819-32
Weinger, Jason G; Greenberg, Milton L; Matheu, Melanie P et al. (2015) Two-photon imaging of cellular dynamics in the mouse spinal cord. J Vis Exp :
Plaisted, Warren C; Weinger, Jason G; Walsh, Craig M et al. (2014) T cell mediated suppression of neurotropic coronavirus replication in neural precursor cells. Virology 449:235-43
Greenberg, Milton L; Weinger, Jason G; Matheu, Melanie P et al. (2014) Two-photon imaging of remyelination of spinal cord axons by engrafted neural precursor cells in a viral model of multiple sclerosis. Proc Natl Acad Sci U S A 111:E2349-55
Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F et al. (2014) Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies. Expert Rev Neurother 14:1169-79
Chucair-Elliott, Ana J; Conrady, Christopher; Zheng, Min et al. (2014) Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia 62:1418-34
Weinger, Jason G; Plaisted, Warren C; Maciejewski, Sonia M et al. (2014) Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis. Stem Cells 32:2690-701
Libbey, Jane E; Lane, Thomas E; Fujinami, Robert S (2014) Axonal pathology and demyelination in viral models of multiple sclerosis. Discov Med 18:79-89

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