title: 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.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, University of Marburg, Marburg, Germany.
authors.forename: Sanchaita Sriwal
authors.initials: SS
authors.lastname: Sonar
authors.forename: Yen-Ming
authors.initials: YM
authors.lastname: Hsu
authors.forename: Melanie Lynn
authors.initials: ML
authors.lastname: Conrad
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Majeau
authors.forename: Ayse
authors.initials: A
authors.lastname: Kilic
authors.forename: Ellen
authors.initials: E
authors.lastname: Garber
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Chioma
authors.initials: C
authors.lastname: Nwankwo
authors.forename: Gundi
authors.initials: G
authors.lastname: Willer
authors.forename: Jan C
authors.initials: JC
authors.lastname: Dudda
authors.forename: Hellen
authors.initials: H
authors.lastname: Kim
authors.forename: Véronique
authors.initials: V
authors.lastname: Bailly
authors.forename: Axel
authors.initials: A
authors.lastname: Pagenstecher
authors.forename: Paul D
authors.initials: PD
authors.lastname: Rennert
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D010718:Phosphatidylserines / Q000378:metabolism; D011991:Receptors, Virus / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; C491143:HAVCR1 protein, human; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D011991:Receptors, Virus