Project Details
Description
There is a critical unmet need to identify the pathogenic mechanisms that drive disease progression in patients
with multiple sclerosis (MS). Accumulation of axon injury and functional disability in MS are not adequately
impacted by current therapies. The long-term goal of this work is to discover new strategies to prevent or
reverse disease progression in MS. Despite evidence that CD8+ T cells are associated with axon injury and
progression in MS, the functional role for these cells and the relevant mechanisms required for recruitment of
these cells to the demyelinated brain are unknown. The antigenic targets of neuron-specific CD8+ T cells are
also unknown. The overall objectives of this study are to test the mechanistic role of neuron antigen-specific
CD8+ T cells in the injury of demyelinated axons and to determine whether patients with MS have such cells.
The rationale is that axon injury is the primary substrate of progression in MS, axonal MHC class I expression
is upregulated by inflammation and demyelination, and cytotoxic CD8+ T cells directed against neuron-specific
antigens injure demyelinated axons. The central hypothesis of this proposal is that neuron antigen-specific
CD8+ T cells injure demyelinated axons. Guided by strong preliminary evidence, the hypothesis will be tested
using AAV-mediated transduction of neurons to drive expression of the neoantigen ovalbumin (OVA) within the
context of CNS demyelination induced by cuprizone toxicity or immunization against a myelin oligodendrocyte
glycoprotein-derived peptide (MOG-EAE) in hosts that have transgenic CD8+ T cells directed against the OVA-
derived peptide SIINFEKL (OT-I). The study will also use autologous T cells and fibroblast-derived iPSC-
derived neurons grown in microfluidic chambers to determine whether MS patient CD8+ T cells injure their own
axons. Three specific aims will be pursued: 1) determine the mechanisms of CD8+ T cell-mediated axon injury
in the demyelinated CNS; 2) identify the cellular locus of MHC class I expression required for axon injury and
determine how demyelination drives CNS infiltration of neuron antigen-specific CD8+ T cells; 3) determine
whether MS patients have neuron-antigen specific CD8+ T cells. This approach is conceptually innovative
because of the proposal that demyelination and inflammation induce axonal presentation of self-peptides on
MHC class I. The approach is technically innovative based on the use of novel AAV vectors to drive
neoantigens in neurons within the demyelinated CNS, selective deletion of brain-resident antigen presenting
cells (APCs) vs peripheral APCs, use of multiple host manipulations coupled to adoptive transfer of traceable
effector cells to temporally and spatially profile anti-neuronal T cell trafficking, and the use of patient-derived
neurons and autologous CD8+ T cells. This work will make a significant, powerful impact on the field by
revealing the capacity of CD8+ T cells directed against neuron-specific antigens to injure demyelinated axons
and by identifying such T cells in patients with MS.
Status | Finished |
---|---|
Effective start/end date | 7/15/20 → 4/30/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $594,747.00
- National Institute of Neurological Disorders and Stroke: $594,747.00
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