Svendsen Pia, Graversen Jonas H, Etzerodt Anders, Hager Henrik, Røge Rasmus, Grønbæk Henning, Christensen Erik I, Møller Holger J, Vilstrup Hendrik, Moestrup Søren K
Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Centre d'Immunologie de Marseille-Luminy (CIML), 13009 Marseille, France.
Mol Ther Methods Clin Dev. 2016 Dec 24;4:50-61. doi: 10.1016/j.omtm.2016.11.004. eCollection 2017 Mar 17.
Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.
高热量碳水化合物的摄入量增加在很大程度上导致了人类地方性非酒精性脂肪性肝病，其组织学范围涵盖从脂肪肝到脂肪性肝炎。高热量摄入以及果糖的脂肪生成作用和内毒素驱动的肝巨噬细胞激活被认为对疾病进展至关重要。在本研究中，我们表明，低剂量的抗CD163-IgG-地塞米松偶联物靶向枯否细胞和其他M2型巨噬细胞中的血红蛋白清除受体CD163，对高果糖饮食大鼠的肝脏炎症变化有深远影响。该饮食在几周内诱导出严重的非酒精性脂肪性肝炎（NASH）样变化，但抗体-药物偶联物显著减轻了炎症、肝细胞气球样变、纤维化和糖原沉积。未偶联的地塞米松或与对照IgG偶联的地塞米松没有这种效果，反而加剧了肝脏脂质积累。低剂量的抗CD163-IgG-地塞米松偶联物未显示出明显的全身副作用。总之，通过抗体导向的抗炎低剂量糖皮质激素疗法靶向巨噬细胞似乎是安全治疗果糖诱导的肝脏炎症的一种有前景的方法。
