Although multiple sclerosis (MS) is the most common neurological disorder to afflict young adults, much remains unknown with regard to the etiology and pathogenesis of this disease. Epidemiologic evidence indicates that there are environmental, gender and genetic factors that influence disease incidence. Nevertheless, the triggering event that initiates the autoimmune response against the myelin sheath is unclear. MS usually begins as a remitting/relapsing inflammatory demyelinating disorder, but in most individuals the disease progresses to a chronic neurological condition that correlates with the accumulation of axonal damage. To further our understanding of this disorder, we have developed a new mouse model of inducible, widespread oligodendrocyte ablation by inducing expression of diptheria toxin A under control of the PLP promoter that results in extensive CNS demyelination in adult animals (DTA model). Strikingly, these animals display robust CNS remyelination that correlates with the recovery from the severe neurological symptoms that the mice display at the peak of disease. At the peak of the early disease course the blood brain barrier remains intact, T cells are not detected within the CNS and axons are preserved. Despite the robust early recovery that these animals display in response to oligodendrocyte (ODC) ablation, within 6 months they succumb to a severe inflammatory neurological condition supporting the `inside-out' model of MS pathogenesis. This late phase progressive disease is characterized by CNS accumulation of myelin-specific CD4+ T cells and widespread focal demyelination. We propose to utilize the DTA model to study fundamental aspects of adult-onset remyelination and demyelination. We will test the hypothesis that the initial CD4+ T cell response to ODC ablation is protective/regulatory, but eventual loss of myelin peptide-specific tolerance/regulation leads to the induction of CD4+ T cell-mediated late-onset disease. We will explore the role that both innate and adaptive immune responses play in development of chronic inflammatory demyelination. While our previously published work shows that there is an increase in the number and activation of CD11b+ cells in the CNS following initial ODC ablation, the question remains whether microglia or peripheral macrophages/DCs are the predominant antigen presenting cells that activate the later influx of pathogenic CD4+ T cells. We will also determine, similar to MS pathogenesis, why there is a lengthy lag time between the initial ODC ablation and the late-onset CD4+ T cell-mediated chronic demyelinating phase. To define the immune mechanisms underlying the transition to late-onset T cell-mediated demyelination, we will exploit strategies to increase the frequency and infiltration of myelin-specific effector and regulatory T cells into the CNS of the DTA mice during the initial disease phase. We will also elucidate the underlying immunopathologic T cell mechanism(s) driving late-onset immune- mediated demyelination. These studies will examine the exciting possibility that the initial ODC loss and demyelination trigger autoreactive myelin-specific T cell responses in a model of chronic progressive MS.
The proposed studies are designed to determine the cellular mechanism(s) by which the death of oligodendrocytes within the CNS results in the eventual activation of myelin peptide-specific CD4+ T cells. The late-onset disease in DTA mice is characterized by widespread demyelination, axonal loss and persistent clinical deterioration, which is reminiscent of the progressive phase of multiple sclerosis (MS). These findings suggest that the DTA mouse model should provide critical insights into the pathogenesis and therapy of chronic progressive MS using a novel animal model of the disease.
| Chen, Yanan; Popko, Brian (2018) Cholesterol crystals impede nerve repair. Science 359:635-636 |
| Ifergan, Igal; Davidson, Todd S; Kebir, Hania et al. (2017) Targeting the GM-CSF receptor for the treatment of CNS autoimmunity. J Autoimmun 84:1-11 |
