Immunotherapy targeting 4-1BB and its ligand

Int J Hematol. 2006 Jan;83(1):23-8. doi: 10.1532/IJH97.05125.

Abstract

T-cell activation in the absence of costimulation is futile because T-cells deprived of costimulatory signals enter a state of unresponsiveness or anergy. The interaction of 4-1BB and 4-1BB ligand (4-1BBL) activates an important costimulatory pathway with diverse and important roles in immune regulation. Signals relayed through 4-1BB generate strong CD8(+) T-cell responses rather than CD4(+) T-cell responses; this action results in cytokine induction and promotes T-cell survival. In recent years, 4-1BB-mediated immune regulation has gained great significance because of the seemingly contradictory dual roles of agonistic anti-4-1BB in vivo disease models. To date, agonistic 4-1BB monoclonal antibody has shown therapeutic potential against a variety of tumors, CD4(+) T-cell-mediated autoimmune diseases, and chronic graft-versus-host disease. In addition, blockade of 4-1BB/4-1BBL interaction has produced therapeutic effects against coxsackievirus-induced myocardial inflammation, herpetic stromal keratitis, and graft rejection. We propose that the dual roles of agonistic anti-4-1BB--an enhanced effector function and a suppressor function--are mediated by a novel CD11c(+)CD8(+) T-cell population.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use
  • Antigens, CD / immunology*
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Coxsackievirus Infections / drug therapy
  • Coxsackievirus Infections / immunology
  • Coxsackievirus Infections / pathology
  • Graft Rejection / drug therapy
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Graft vs Host Disease / drug therapy
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / pathology
  • Humans
  • Immunotherapy*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Receptors, Nerve Growth Factor / antagonists & inhibitors
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factors / immunology*

Substances

  • 4-1BB Ligand
  • Antibodies, Monoclonal
  • Antigens, CD
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • TNFSF9 protein, human
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Necrosis Factors