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

Authors: Sonar, SS  Hsu, YM  Conrad, ML  Majeau, GR  Kilic, A  Garber, E  Gao, Y  Nwankwo, C  Willer, G  Dudda, JC  Kim, H  Bailly, V  Pagenstecher, A  Rennert, PD  Renz, H 
Citation: Sonar SS, etal., J Clin Invest. 2010 Aug 2;120(8):2767-81. doi: 10.1172/JCI39543. Epub 2010 Jul 12.
Pubmed: (View Article at PubMed) PMID:20628202
DOI: Full-text: DOI:10.1172/JCI39543

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.

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CRRD Object Information
CRRD ID: 5128851
Created: 2011-03-21
Species: All species
Last Modified: 2011-03-21
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.