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Systemic Treatment with a miR‐146a Mimic Suppresses Endotoxin Sensitivity and Partially Protects Mice from the Progression of Acute Graft‐versus‐Host Disease
Author(s) -
Gartner J. G.,
Durston M. M.,
Booth S. A.,
Ellison C. A.
Publication year - 2017
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/sji.12597
Subject(s) - in vivo , intestinal permeability , inflammation , immunology , graft versus host disease , ex vivo , tumor necrosis factor alpha , biology , disease , medicine , pathology , microbiology and biotechnology
Abstract Acute GVHD ( aGVHD ) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS , secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that micro RNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD . Using the C57 BL /6 → (C57 BL /6 × DBA /2)F 1 ‐hybrid model of aGVHD , we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain micro RNA s (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD ‐associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR‐146a and treated recipient mice systemically with a miR‐146a mimic early in the GVH reaction. This led to a reduction in the burst of IFN γ that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS ‐induced TNF α release and GVHD ‐associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR‐146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD.