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

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 describ...

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Bibliographic Details
Published in:The Journal of clinical investigation 2010-08, Vol.120 (8), p.2767-2781
Main Authors: Sonar, Sanchaita Sriwal, Hsu, Yen-Ming, Conrad, Melanie Lynn, Majeau, Gerard R, Kilic, Ayse, Garber, Ellen, Gao, Yan, Nwankwo, Chioma, Willer, Gundi, Dudda, Jan C, Kim, Hellen, Bailly, Véronique, Pagenstecher, Axel, Rennert, Paul D, Renz, Harald
Format: Article
Language:English
Subjects:
Allergens
Allergies
Animals
Antibodies
Antibodies, Monoclonal - therapeutic use
Asthma
Asthma - immunology
Asthma - prevention & control
Biomedical research
CD4-Positive T-Lymphocytes - immunology
Cytokines
Dendritic Cells - metabolism
Development and progression
Disease
Disease Models, Animal
Female
Gene expression
Genetic aspects
Hepatitis A Virus Cellular Receptor 1
Humans
Immunoglobulins
Inflammation
Ligands
Lymphocyte Activation
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - physiology
Membrane Proteins - antagonists & inhibitors
Membrane Proteins - physiology
Mice
Mice, SCID
Mucins
Phosphatidylserines - metabolism
Physiological aspects
Properties
Proteins
Receptors, Virus - antagonists & inhibitors
Receptors, Virus - physiology
T cells
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci39543