Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS.
Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a multiple sclerosis (MS) model, is a central nervous system (CNS) demyelinating disease characterized by early peripheral T cell responses to virus epitopes which spreads to myelin epitopes during chronic disease. We show that CD4(+) T cells isolated from the spinal cords of chronically infected SJL mice proliferate and secrete pro-inflammatory cytokines upon in vitro challenge with both TMEV epitopes and proteolipid protein (PLP(139-151)). Importantly, myelin-specific tolerance induced by intravenous administration of MP4, a fusion of the myelin proteins myelin basic protein (MBP) and PLP, to SJL mice with ongoing TMEV-IDD attenuated disease progression and resulted in significantly less demyelination and decreased inflammatory cell infiltration in the CNS. Paradoxically, peptide-specific splenic T cell proliferative and IFN-gamma responses were enhanced in the tolerized mice. Collectively, these results indicate that myelin-specific T cell responses contribute to chronic disease progression in this virus-induced model of MS, and suggest caution in the use of antigen-specific tolerance for treatment of ongoing autoimmune disease.
Neville
Katherine L
KL
Department of Microbiology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Padilla
Josette
J
Miller
Stephen D
SD
D000595:Amino Acid Sequence; D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000517:prevention & control*; D000939:Epitopes; D005260:Female; D006968:Hypersensitivity, Delayed / Q000517:prevention & control; D007108:Immune Tolerance; D051379:Mice; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000628:therapy*; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein / Q000276:immunology; D009186:Myelin Sheath / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D017945:Theilovirus / Q000276:immunology*
D016207:Cytokines; D000939:Epitopes; C101821:MP4 protein, chimeric; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C435023:myelin proteolipid protein (139-151)