Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

J Clin Invest. 2010 Aug;120(8):2767-81. doi: 10.1172/JCI39543. Epub 2010 Jul 12.

Abstract

Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Asthma / immunology
  • Asthma / prevention & control*
  • CD4-Positive T-Lymphocytes / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Female
  • Hepatitis A Virus Cellular Receptor 1
  • Humans
  • Lymphocyte Activation
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / physiology
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / physiology
  • Mice
  • Mice, SCID
  • Phosphatidylserines / metabolism
  • Receptors, Virus / antagonists & inhibitors*
  • Receptors, Virus / physiology

Substances

  • Antibodies, Monoclonal
  • HAVCR1 protein, human
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphatidylserines
  • Receptors, Virus