Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice.

Autor:	Yalamanoglu A; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Dubach IL; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Schulthess N; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Ingoglia G; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Swindle DC; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Aurora, CO, United States., Humar R; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Schaer DJ; Division of Internal Medicine, University of Zurich, Zurich, Switzerland., Buehler PW; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, United States.; Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States., Irwin DC; Cardiovascular and Pulmonary Research Laboratory, Department of Medicine, University of Colorado Denver, Aurora, CO, United States., Vallelian F; Division of Internal Medicine, University of Zurich, Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Mar 04; Vol. 12, pp. 627944. Date of Electronic Publication: 2021 Mar 04 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.627944
Abstrakt:	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, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Yalamanoglu, Dubach, Schulthess, Ingoglia, Swindle, Humar, Schaer, Buehler, Irwin and Vallelian.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu