Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma
Sanchaita Sriwal Sonar, … , Paul D. Rennert, Harald Renz
Sanchaita Sriwal Sonar, … , Paul D. Rennert, Harald Renz
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2767-2781. https://doi.org/10.1172/JCI39543.
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Research Article Immunology

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

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Figure 1

Binding and blocking activities of anti–TIM-1 mAbs.

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Binding and blocking activities of anti–TIM-1 mAbs. (A) Representative E...
(A) Representative ELISA binding curve showing anti-human TIM-1 mAb A6G2 binding to immobilized human TIM-1–Fc. The relative EC50 after curve fitting was calculated to be 4 ng/ml (26.7 pM). (B and C) Reduction of TIM-1 binding to PS by anti–TIM-1 mAbs. Anti-mouse TIM-1 mAb 4A2 reduced the binding of murine TIM-1–Fc to PS by 63% (B), while anti-human TIM-1 mAb A6G2 reduced the binding of human TIM-1–Fc to PS by 78% (C).