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.
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.
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