Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice
نویسندگان
چکیده
Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the β-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, increased adhesive properties to endothelium. In proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related sickling process, acute sickle hepatic crisis, observed about 10% of crisis incidents. mice, ligation CD40 agonistic antibody leads macrophage activation liver, triggering sequence systemic activation, thrombosis, focal ischemia. We found that anti-CD40 injection mice induces inflammatory hemodynamic response accelerated hemolysis, extensive vaso-occlusion, large ischemic infarctions liver mimicking crisis. Administration tumor necrosis factor-α (TNF-α) blocker, etanercept, heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest administration offers novel model humanized allowing for evaluation therapeutic proof-of-concept.
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ژورنال
عنوان ژورنال: Frontiers in Immunology
سال: 2021
ISSN: ['1664-3224']
DOI: https://doi.org/10.3389/fimmu.2021.627944