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 2

TIM-1 protein binding to DCs and blockade using anti–TIM-1 mAbs.

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TIM-1 protein binding to DCs and blockade using anti–TIM-1 mAbs. (A) Bin...
(A) Binding of murine TIM-1–Fc to bone marrow–derived murine myeloid DCs in the presence or absence of EGTA and the anti-mouse TIM-1 mAb 4A2. TIM-1 binding was reduced by EGTA and by mAb 4A2. (B) Binding of murine TIM-1–IgV–Fc to bone marrow–derived murine myeloid DCs in the presence or absence of the anti-mouse TIM-1 mAb 4A2. The IgV domain was sufficient to mediate binding to myeloid DCs, and this binding was reduced by anti-mouse TIM-1 mAb 4A2. (C) Binding of murine TIM-1–Fc to LPS-activated bone marrow–derived murine myeloid DCs in the presence or absence of EGTA and the anti-mouse TIM-1 mAb 4A2. LPS activation increases TIM-1 binding to myeloid DCs, and this increased binding was reduced by EGTA and by anti-mouse TIM-1 mAb 4A2. (D) Binding of human TIM-1–Fc to human CD34+ stem cell–derived myeloid DCs in the presence or absence of EGTA and the anti-human TIM-1 mAb A6G2. TIM-1 binding was reduced by EGTA and by the anti-human TIM-1 mAb A6G2.