一种对抗乙型肝炎的新型免疫治疗方法2021 年 6 月 22 日 |肝病学在全球范围内，慢性乙型肝炎病毒 (HBV) 感染与大量肝脏相关的发病率和死亡率有关，估计导致 800,000 人死于肝硬化和肝细胞癌等并发症。现在，英国伦敦大学学院 (UCL) 的研究人员确定了一种新的免疫治疗策略，可以改变 HBV 的治疗格局。主要作者、伦敦大学学院感染和免疫学部病毒免疫学教授 Mala Maini 强调了该研究的相关性：“新型治疗药物的开发对于改善患者护理至关重要。免疫细胞（如 T 细胞）对于对抗病毒和肿瘤是必不可少的，但通常功能失调且无法控制这些疾病。目前的护理标准通常无法消除病毒，不能预防癌症的发展，也不能拯救免疫细胞。” Maini 补充说：“在这项研究中，我们的目标是确定一个治疗目标，以直接抑制病毒，同时增强免疫细胞的抵抗力。”该研究使用从 HBV 感染的肝组织中直接分离的免疫细胞来证明阻断酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 的活性是增强免疫反应的一种非常有效的方法。具体而言，发现 ACAT 抑制剂可增强人类抗原特异性反应并挽救 CD8+ T 细胞功能。此外，作者能够描绘出据信支持这一过程的代谢变化。胆固醇是细胞膜的主要成分，细胞内水平受到严格调控，多余的胆固醇被酯化并储存在细胞质中的中性脂滴中；然而，脂滴的积累会抑制免疫细胞的功能。由于 ACAT 催化胆固醇的酯化，其抑制作用有望减少脂滴的积累。这可能会对抗病毒 CD8+ T 细胞的功能产生有益的影响。第一作者、伦敦大学学院感染和免疫学部的 Nathalie Schmidt 在评论研究结果时指出：“我们发现了一种治疗慢性乙型肝炎病毒感染和肝癌的高效新靶点。” Schmidt 还表示：“众所周知，这种调节胆固醇的药物对人类是安全的，我们希望我们的研究现在可以为将胆固醇调节与其他免疫疗法相结合的临床试验的发展提供信息。总之，我们的发现为治疗慢性病毒感染和癌症患者提供了令人兴奋的新可能性。” 作者: StephenW 时间: 2021-9-22 17:55
A Novel Immunotherapeutic Approach to Combat Hepatitis B
22 June 2021 | Hepatology
GLOBALLY, chronic hepatitis B virus (HBV) infection is associated with substantial liver-related morbidity and mortality, causing an estimated 800,000 deaths from complications such as cirrhosis and hepatocellular carcinoma. Now, a new immunotherapy strategy identified by researchers at University College London (UCL), UK, could transform the treatment landscape of HBV.
Lead author Mala Maini, Professor of Viral Immunology, UCL Division of Infection and Immunology, highlighted the relevance of the research: “The development of novel therapeutic agents is crucial to improve patient care. Immune cells such as T cells are indispensable for fighting viruses and tumours but are often highly dysfunctional and fail to control these diseases. Current standard of care treatments are often incapable of eliminating the virus, do not prevent cancer development and do not rescue immune cells.” Maini added: “In this study we aimed to identify a treatment target to directly inhibit the virus while also boosting the immune cells fighting it.”
The study used immune cells isolated directly from HBV-infected liver tissue to demonstrate that blocking the activity of acyl-CoA:cholesterol acyltransferase (ACAT) was a highly effective way of enhancing immune responses. Specifically, ACAT inhibitors were found to boost human antigen-specific responses and rescue CD8+ T cell function. Furthermore, the authors were able to delineate the metabolic changes believed to underpin this process. Cholesterol is a major component of cell membranes and intracellular levels are tightly regulated, with excess cholesterol esterified and stored in neutral lipid droplets in the cytoplasm; however, the accumulation of lipid droplets can inhibit the function of immune cells. Since ACAT catalyses the esterification of cholesterol, its inhibition would be expected to reduce the accumulation of lipid droplets. This would potentially have a beneficial effect on the functionality of antiviral CD8+ T cells.
Commenting on the research findings, first author Nathalie Schmidt, UCL Division of Infection and Immunology, noted: “We have found a highly effective novel target for the treatment of chronic hepatitis B virus infection and liver cancer.” Schmidt also stated: “The cholesterol-modifying drug is already known to be safe in humans and we hope that our study now informs the development of clinical trials combining cholesterol modulation with other immunotherapies. In summary, our findings offer exciting new possibilities for the treatment of patients with chronic viral infections and cancer.”