UC Irvine

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease for which there is no cure. Compelling evidence from animal models of immune-mediated demyelination suggests transplanted neural precursor cells (NPCs) dampen neuroinflammation and promote remyelination, resulting in improved clinical outcome. However, much of the work evaluating NPC transplantation has been conducted using grafts from genetically identical donors or immune suppressed subjects. From a clinical perspective, NPCs are most likely to be genetically mismatched (allogeneic), and systemic immune suppression increases the risk of peripheral infection for the host. Therefore, when considering NPC transplantation for MS, the potential for engrafted cells to elicit an immune response, the consequences of engraftment in an environment with ongoing inflammation, and the susceptibility of NPCs to infection must be evaluated.

The focus of this dissertation is to elucidate mechanisms of immune rejection and repair following transplantation of NPCs in a virus-induced model of neuroinflammatory demyelination. Inoculation of susceptible mice with the neuroattenuated JHM variant of mouse hepatitis virus (MHV) induces acute encephalomyelitis followed by chronic immune-mediated demyelination that recapitulates histopathological and clinical features of MS. Using this well-accepted model, we demonstrate that allogeneic NPCs are antigenic and are rejected following transplantation. Rejection is correlated with expression of major histocompatibility complex (MHC) and co-stimulatory molecules by NPCs, as well as increased CD4+ and CD8+ T cell activity in vitro and in vivo (Chapter 2). Additionally, allogeneic NPCs are lysed by natural killer (NK) cells following binding of retinoic acid early inducible-1 (RAE-1) to the NK-activating receptor NKG2D. NK cells localize with allografted NPCs and NK cell infiltration is correlated with reduced graft survival. Furthermore, NPCs can be infected by MHV, which elicits destruction via NK cell-mediated mechanisms (Chapter 3). We provide evidence that CD4+ and CD8+ T cells participate in suppression of virus replication in MHV-infected NPCs via secretion of interferon-gamma (IFN-γ) and direct cytolysis (Chapter 4). Lastly, induced pluripotent stem cells (iPSCs) represent an unlimited source of NPCs that are genetically identical to the host. We demonstrate that NPCs derived from human iPSCs promote focal remyelination concomitant with suppressed CD4+ T cell infiltration in the CNS dependent on increased regulatory T cell (Treg) activity (Chapter 5).