Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma
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
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
View: Text | PDF
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

×

Figure 7

Mechanism of TIM-1 antagonism.

Options: View larger image (or click on image) Download as PowerPoint
Mechanism of TIM-1 antagonism. Nonallergic control (white bars) or asthm...
Nonallergic control (white bars) or asthmatic (black bars) donor samples are indicated as appropriate. (A–D) qPCR of GATA3, cMAF, FoxP3, and Tbet in lung tissue. (E) FACS analysis of IL-4+/CD3+ T cells from control or D. pteronyssinus–stimulated asthmatic donor PBMCs, incubated with mAbs as indicated. (F) Percentage of IL-4–expressing CD3+ T cells in all groups. (G and H) Human IL-4 and IFN-γ levels from asthmatic human PBMC supernatants. (I and J) Proliferation of human PBMCs and hu-PBMC SCID splenic mononuclear cells measured as percent BrdU (percent normalized to unstimulated control). (K and L) Activated CD4+ T cell proliferation and IL-5 production after coculture with D. pteronyssinus plus auto­logous myeloid DCs from nonallergic control and asthmatic donors. In vivo experiments (A–D and J) included nonallergic donor controls and asthmatic donors, alone or treated with mAb as indicated, and represent 3 independent experiments. In vitro analyses (E–I) included an unstimulated asthmatic PBMC control, D. pteronyssinus, or anti-CD3/anti-CD28–stimulated asthmatic PBMCs alone or incubated with mAb. (K–L) Groups for in vitro analysis included nonallergic or asthmatic myeloid DCs plus CD4+ T cells stimulated with D. pteronyssinus with or without mAb; other controls included only nonallergic myeloid DCs or CD4+ cells stimulated with D. pteronyssinus. In vitro data represent 3 independent experiments comprising 4 asthmatic and 4 nonallergic donors per group. Values represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.