Subproject: Brian Popko for Regulation of CD4+ T cell-mediated Demyelination Following Oligo Ablation

Project: Research project

Project Details

Description

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 immunemediated
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.
StatusActive
Effective start/end date7/15/176/30/22

Funding

  • National Institute of Neurological Disorders and Stroke (5R01NS099334-04)

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