Multiple sclerosis (MS) is an autoimmune demyelinating and degenerative disease of the central nervous system (CNS), which is characterized by relapsing-remitting symptoms in the early phase and followed by secondary progression and permanent disability. Myelin associated glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in mice serves as an animal model for human MS. Neural stem cells (NSCs) are a population of immature, undifferentiated multipotent cells in the adult CNS that contribute to the CNS repair and regeneration upon injury or disease. Neural stem cell therapy has been proposed in recent years for CNS repair. Recently, exogenously administered NSCs were reported to suppress EAE through an immune modulatory mechanism. Our initial studies suggest a role of NSCs in mediating regulatory T cell (Treg) expansion as well as suppression of pathogenic T cells differentiation.
The aims for this proposal are: 1) To investigate the mechanisms of NSC-mediated immune suppression in EAE. Our hypothesis is that NSCs alter T cell differentiation in favor of Treg differentiation and suppress pathogenic Th1 and Th17 cells. We will investigate the molecular mechanisms of NSC-mediated Treg expansion and survival. We will also investigate the mechanisms of NSC-mediated suppression of pathogenic Th1 and Th17 cell differentiation and their in vivo correlation. 2) To study NSCs and T cells interaction and migration in vivo. The timing and site of exogenous NSCs interact with T cells may be critical for the outcome of the EAE suppression. Furthermore, the inflammatory cytokines in the pathological environment may stimulate or inhibit NSCs repair. We will investigate the effects of the timing of NSC injection and whether the NSCs suppress pathogenic T cells and promote Treg expansion and migration in the peripheral lymphoid organs or whether the NSCs themselves migrate to the CNS and elicit this effect in situ. We will focus on NSC and T cell trafficking at different stages of EAE and strictly monitor NSC migration, survival, proliferation or differentiation in the recipients. 3) To study the effect of NSCs on modulating the function of antigen-presenting cells. We will examine monocyte/macrophage, microglia and dendritic cell activation and functions under the influence of NSCs in vitro and in vivo during EAE. This experimental plan will allow us to better understand the effects of NSC intervention on the immune system during EAE progression. The results will give valuable insights for using NSC therapeutically. Furthermore, the proposal will provide insight into the interactions of endogenous NSCs with immune cells during autoimmune diseases, and a potential pathway to enhance endogenous repair.

Public Health Relevance

Neural stem cells have been shown to protect from disease and reverse ongoing disease in animal models, but the mechanisms by which this occurs are still controversial. We have observed that neural stem cells enhance regulatory T cells both in vitro and in vivo;so we will investigate the mechanisms by which NSCs enhance regulatory T cells and suppress differentiation of effector cells, where the interaction between NSCs and T cells occur, and whether NSCs affect antigen presenting cell function. These investigations will have an impact on our understanding of the mechanisms of NSCs mediated disease suppression;are critical for therapeutic implementation of NSCs or human diseases such as multiple sclerosis;and furthermore, these studies will provide insight into potential mechanisms to enhance endogenous repair.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Esch, Thomas R
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Brigham and Women's Hospital
United States
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Kurdi, Ahmed T; Bassil, Ribal; Olah, Marta et al. (2016) Tiam1/Rac1 complex controls Il17a transcription and autoimmunity. Nat Commun 7:13048
Bassil, Ribal; Orent, William; Olah, Marta et al. (2014) BCL6 controls Th9 cell development by repressing Il9 transcription. J Immunol 193:198-207