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1.
Front Immunol ; 11: 666, 2020.
Article in English | MEDLINE | ID: mdl-32391007

ABSTRACT

Neutrophilic inflammation occurs during asthma exacerbation, and especially, in patients with steroid-refractory asthma, but the underlying mechanisms are poorly understood. Recently, a significant accumulation of neutrophil extracellular traps (NETs) in the airways of neutrophilic asthma has been documented, suggesting that NETs may play an important role in the pathogenesis. In this study, we firstly demonstrated that NETs could induce human airway epithelial cell damage in vitro. In a mouse asthmatic model of neutrophil-dominated airway inflammation, we found that NETs were markedly increased in bronchoalveolar lavage (BAL), and the formation of NETs exacerbated the airway inflammation. Additionally, a small-molecule drug necrostatin-1 (Nec-1) shown to inhibit NETs formation was found to alleviate the neutrophil-dominated airway inflammation. Nec-1 reduced total protein concentration, myeloperoxidase activity, and the levels of inflammatory cytokines in BAL. Finally, further experiments proved that the inhibition of Nec-1 on NETs formation might be related to its ability to inhibiting mixed lineage kinase domain-like (MLKL) phosphorylation and perforation. Together, these results document that NETs are closely associated with the pathogenesis of neutrophilic asthma and inhibition of the formation of NETs by Nec-1 may be a new therapeutic strategy to ameliorate neutrophil-dominated airway inflammation.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Imidazoles/therapeutic use , Indoles/therapeutic use , Inflammation/drug therapy , Neutrophils/immunology , Protein Kinases/metabolism , Animals , Disease Models, Animal , Extracellular Traps/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Neutrophil Activation , Phosphorylation
2.
MAbs ; 6(5): 1290-9, 2014.
Article in English | MEDLINE | ID: mdl-25517314

ABSTRACT

The CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , CD28 Antigens/immunology , Membrane Proteins/immunology , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Blotting, Western , CD28 Antigens/agonists , CD28 Antigens/metabolism , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Adhesion/drug effects , Cell Adhesion/immunology , Cell Movement/drug effects , Cell Movement/immunology , Cell Proliferation/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelial Cells/metabolism , Flow Cytometry , Humans , Immunologic Memory/immunology , Lymphocyte Function-Associated Antigen-1/immunology , Lymphocyte Function-Associated Antigen-1/metabolism , Membrane Proteins/metabolism , Microscopy, Fluorescence , Programmed Cell Death 1 Receptor/metabolism , Receptors, CCR5/immunology , Receptors, CCR5/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , Up-Regulation/drug effects , Up-Regulation/immunology
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