title: Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cells.
abstract: Multiple sclerosis (MS) is a T-cell mediated autoimmune disease of the CNS, possessing both immune and neurodegenerative events that lead to disability. Adoptive transfer (AT) of myelin basic protein (MBP)-specific T cells into naïve female SJL/J mice results in a relapsing-remitting (RR) form of experimental autoimmune encephalomyelitis (EAE). Blocking the mechanisms by which MBP-specific T cells are activated before AT may help characterize the immune arm of MS and offer novel targets for therapy. One such target is calpain, which is involved in activation of T cells, migration of immune cells into the CNS, degradation of axonal and myelin proteins, and neuronal apoptosis. Thus, the hypothesis that inhibiting calpain in MBP-specific T cells would diminish their encephalitogenicity in RR-EAE mice was tested. Incubating MBP-specific T cells with the calpain inhibitor SJA6017 before AT markedly suppressed the ability of these T cells to induce clinical symptoms of RR-EAE. These reductions correlated with decreases in demyelination, inflammation, axonal damage, and loss of oligodendrocytes and neurons. Also, calpain : calpastatin ratio, production of truncated Bid, and Bax : Bcl-2 ratio, and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated. Thus, these data suggest calpain as a promising target for treating EAE and MS.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Guyton
authors.forename: Saurav
authors.initials: S
authors.lastname: Brahmachari
authors.forename: Arabinda
authors.initials: A
authors.lastname: Das
authors.forename: Supriti
authors.initials: S
authors.lastname: Samantaray
authors.forename: Jun
authors.initials: J
authors.lastname: Inoue
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Azuma
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001896:Boron Compounds / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D003711:Demyelinating Diseases / Q000175:diagnosis / Q000209:etiology / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D004676:Myelin Basic Protein / Q000096:biosynthesis*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
chemical_list: D001896:Boron Compounds; D002135:Calcium-Binding Proteins; D004151:Dipeptides; D004676:Myelin Basic Protein; C109145:N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal; C033668:calpastatin; C045000:dicesium N-succinimidyl 3-(undecahydrododecaboranyldithio)propionate; D007770:L-Lactate Dehydrogenase; D002154:Calpain