title: CTLA-4 downregulates epitope spreading and mediates remission in relapsing experimental autoimmune encephalomyelitis.
abstract: During the progression of relapsing experimental autoimmune encephalomyelitis (R-EAE), in SJL mice, disease relapses are mediated by T cells specific for non-cross-reactive myelin epitopes, a process termed 'epitope spreading'. CTLA-4, a negative regulator of T cell function modulates R-EAE, in that CTLA-4 blockade exacerbates clinical R-EAE. Herein, we show that CTLA-4-mediated signaling negatively regulates the dynamic spread of autoreactive T cell responses during the course of autoimmune disease. Anti-CTLA-4 mAb, administration at various points during the progression of R-EAE exacerbated subsequent clinical disease and enhanced T cell reactivity to both inducing and relapse-associated epitopes. In addition, CTLA-4 blockade during acute disease inhibited clinical remission. Thus, CTLA-4-mediated events are critical for intrinsic regulation of epitope spreading during autoimmune disease.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: T N
authors.initials: TN
authors.lastname: Eagar
authors.forename: C L
authors.initials: CL
authors.lastname: Vanderlugt
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000069594:Abatacept; D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D060908:CTLA-4 Antigen; D003429:Cross Reactions; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007114:Immunization; D018796:Immunoconjugates; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology; D010743:Phospholipids / Q000737:chemistry / Q000276:immunology; D012008:Recurrence; D012075:Remission, Spontaneous; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D004676:Myelin Basic Protein; D010743:Phospholipids; D000069594:Abatacept