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

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.

• Authors: Sanchaita Sriwal Sonar, Yen-Ming Hsu, Melanie Lynn Conrad, Gerard R Majeau, Ayse Kilic, Ellen Garber, Yan Gao, Chioma Nwankwo, Gundi Willer, Jan C Dudda, Hellen Kim, Véronique Bailly, Axel Pagenstecher, Paul D Rennert, Harald Renz
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 8 Pg. 2767-81 (Aug 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20628202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Asthma (immunology, 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, physiology)
• Membrane Proteins (antagonists & inhibitors, physiology)
• Mice
• Mice, SCID
• Phosphatidylserines (metabolism)
• Receptors, Virus (antagonists & inhibitors, physiology)