Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ–δ T cells are critical for the development of PE-like features in mice since γ–δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ–δ T cells. These preclinical data demonstrate that CLIP expression and activated γ–δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ–δ T cells may be a therapeutic strategy for PE.
Depletion of MHC class II invariant chain peptide or γ–δ T-cells ameliorates experimental preeclampsia
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Piyali Chatterjee, Valorie L. Chiasson, Geetha Seerangan, Eugene De Guzman, Moheb Milad, Kelsey R. Bounds, Olga Gasheva, Richard P. Tobin, Mohamad Hatahet, Shelley Kopriva, Kathleen A. Jones, M. Karen Newell-Rogers, Brett M. Mitchell; Depletion of MHC class II invariant chain peptide or γ–δ T-cells ameliorates experimental preeclampsia. Clin Sci (Lond) 1 August 2017; 131 (15): 2047–2058. doi: https://doi.org/10.1042/CS20171008
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