title: Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE.
abstract: Relapsing experimental autoimmune encephalomyelitis (R-EAE) induced with the immunodominant epitope from proteolipid protein, PLP139-151, is characterized by the development of recurrent relapses with recruitment of T cells reactive to additional myelin peptides, including PLP178-191 (epitope spreading). In this study, we have determined that the CD28/B7 costimulatory pathway is involved in this process. We found preferential up-regulation of B7-1 during the course of R-EAE and a selective increase in its functional costimulatory activity, relative to B7-2. Anti B7-1 F(ab) fragment therapy, but not anti B7-2 MAb therapy, blocked clinical relapses, ameliorated CNS pathology, and blocked epitope spreading. These results suggest that the maintenance of autoimmune reactivity in EAE depends on CD28/B7-1-dependent costimulation of newly recruited T cells responsible for epitope spreading. These studies have important implications for the role of epitope spreading in disease progression and the clinical application of costimulatory antagonists in autoimmune diseases.
authors.affiliation: Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Miller
authors.forename: C L
authors.initials: CL
authors.lastname: Vanderlugt
authors.forename: D J
authors.initials: DJ
authors.lastname: Lenschow
authors.forename: J G
authors.initials: JG
authors.lastname: Pope
authors.forename: N J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: M C
authors.initials: MC
authors.lastname: Dal Canto
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D051379:Mice; D009185:Myelin Proteins / Q000276:immunology*; D051381:Rats; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; D009185:Myelin Proteins