Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis

J Immunol. 2002 Feb 1;168(3):1457-65. doi: 10.4049/jimmunol.168.3.1457.

Abstract

4-1BB, a member of the TNFR superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB Abs enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of an agonistic anti-4-1BB mAb (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Adoptive transfer of T cells from such treated mice failed to induce EAE, whereas anti-4-1BB treatment following adoptive transfer of encephalitogenic T cells did not prevent EAE pathogenesis. These results suggest that anti-4-1BB treatment during the induction phase inhibits autoreactive T cell immune responses rather than preventing T cell trafficking into the CNS. This was substantiated by the observations that draining lymph node cells from anti-4-1BB-treated mice failed to respond to Ag stimulation in vitro. In addition, we found that such treatment initially promotes the activation and proliferation of Ag-specific CD4+ T cells but subsequently increases their probability of undergoing activation-induced cell death, thereby inhibiting effector T cell responses. More importantly, 2A treatment also inhibits the relapse of EAE in a clinically relevant murine model of multiple sclerosis. This study indicates that the agonistic Ab against 4-1BB can potentially be used as a novel immunotherapeutic agent for treating autoimmune diseases.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Encephalomyelitis, Autoimmune, Experimental / etiology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Immunization Schedule
  • Injections, Intraperitoneal
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myelin Proteins
  • Myelin-Associated Glycoprotein / antagonists & inhibitors
  • Myelin-Associated Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein
  • Receptors, Nerve Growth Factor / agonists*
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / agonists*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Secondary Prevention
  • T-Lymphocyte Subsets / transplantation
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9