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.

Characterizing Functional Domains for TIM-Mediated Enveloped Virus Entry

“…Transfected HEK 293T cells were detached with 1ϫ PBS plus 5 mM EDTA 48 h after transfection, washed with 1ϫ PBS plus 5% FBS, and incubated for 1 h with goat polyclonal antisera specific to mTIM-1, TIM-1, TIM-3, or TIM-4 as indicated (R&D Systems) at a concentration of 4 g/ml. Alternatively, cells were incubated for 1 h with human TIM-1 specific mouse monoclonal antibodies (MAbs) ARD5 or AKG7 (4,18,19) as indicated at a concentration of 5 g/ml. Normal goat serum or purified mouse IgG2a (R&D Systems) were used as negative controls.…”

Effect of continuous renal replacement therapy on kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in patients with septic acute kidney injury

“…Kim-1 is a member of the immunoglobulin family and is expressed in the surface of activated T cells (CD4 + Th2) (32); therefore, sKim-1 may be involved in the immune response to sepsis and its level is higher than normal in this condition. Previous animal and clinical studies have demonstrated (33,34) that Kim-1 is an inflammation mediator associated with the pathogenesis of asthma and rheumatoid arthritis. A prospective, multicenter cohort study (35) found that Kim-1 peaked at 2 days after cardiac surgery in adults and at 1 day after surgery in children, and that the elevations of Kim-1 were associated with AKI and adverse outcomes in adults.…”

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

“…Anti‐TIM‐1 antibody (Clone RMT1‐10) ameliorates Experimental autoimmune encephalomyelitis (EAE),17 allergic asthma,37 glomerulonephritis38 and corneal allograft rejection 39. In contrast another anti‐TIM‐1 antibody (clone 3B3) enhances T cell proliferation and Th2 effector function 17, 40, 41.…”