A novel mouse model for progressive multiple sclerosis

Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the CNS. Although the majority of patients are diagnosed with relapsing remitting MS, many of these patients later develop a chronic progressive form of MS, for which there is no well-established mouse model. TNF-alpha signaling through the TNFR2 receptor has been shown to have an important role in the remyelination process and mice deficient for TNFR2 have been shown to have increased disease severity. The aim of this study was to evaluate TNFR2-/- mice, transgenic for the MS associated HLA-DR2b haplotype, for their potential use as a model for chronic progressive MS. The HLA-DR2b+/+TNFR2-/- mice exhibited a chronic EAE disease course as indicated by clinical score and weight loss, as compared to HLA-DR2b+/+ control mice. Additionally, the HLA-DR2b+/+TNFR2-/- mice had chronic and progressive ataxia symptoms as compared to the HLA-DR2b+/+mice. Our studies also indicate that the HLA-DR2b+/+TNFR2-/- mice had higher levels of IL-17 producing Ag-specific T cells in the brain, beginning from the disease peak, fewer CD19+ cells in the spleen of naïve animals and, no CD8+ cells in the CNS at disease peak, suggesting disruption in regulatory-cell functions in these animals. Immunohistochemistry analysis revealed more lesions in the cerebellum and spinal cord of the HLA-DR2b+/+TNFR2-/- with CD11b+ cells dispersed around the lesions during the disease peak as compared to the HLA-DR2b+/+ mice.