CTLA-4 downregulates epitope spreading and mediates remission in relapsing experimental autoimmune encephalomyelitis

J Neuroimmunol. 2000 Sep 22;109(2):173-80. doi: 10.1016/s0165-5728(00)00322-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abatacept
  • Acute Disease
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD
  • Antigens, Differentiation / immunology*
  • Autoantigens / immunology
  • CTLA-4 Antigen
  • Cross Reactions
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • Flow Cytometry
  • Hypersensitivity, Delayed / immunology
  • Immunization
  • Immunoconjugates*
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Myelin Basic Protein / chemistry
  • Myelin Basic Protein / immunology
  • Phospholipids / chemistry
  • Phospholipids / immunology
  • Recurrence
  • Remission, Spontaneous
  • T-Lymphocytes / immunology

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • Autoantigens
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Epitopes, T-Lymphocyte
  • Immunoconjugates
  • Myelin Basic Protein
  • Phospholipids
  • Abatacept