Metabolic regulation of hepatic immunopathology by myeloid-derived suppressor cells

据估计，世界上约有三分之一的人口接触过乙肝病毒，至少有3.5亿人仍处于慢性感染状态。由此导致的肝病包括肝硬变和肝癌，每年导致100多万人死亡。现有的治疗方法很少能达到治愈的效果。因此，患者需要接受长期治疗，这对许多感染最普遍的国家来说仍然是负担不起的，而且存在病毒耐药性和毒性的风险。肝癌是癌症相关死亡的第三大常见原因，对它的治疗仍然非常有限。我们的工作重点是了解如何提高人体的自然免疫力，以实现对乙肝病毒和肝癌等并发症的控制。我们认为这应该是可以实现的，因为许多感染了乙肝病毒的成年人，自然会产生一种免疫反应，在他们的余生中成功地控制它。众所周知，T细胞对控制像乙肝病毒这样的病毒至关重要，在慢性感染患者中，T细胞的数量和功能受到严重损害。我们已经发现，他们的T细胞不能扩张和正常工作的一个原因是他们缺乏精氨酸等关键营养物质。我们的新发现揭示了另一种特殊的免疫细胞类型，称为“髓系来源的抑制细胞”，剥夺了T细胞的营养，从而阻碍了它们的反应。这些抑制细胞有助于抑制肝脏的免疫反应，以阻止它们破坏这个重要的器官，但这样做会损害对乙肝病毒等病原体的控制。我们现在建议更全面地定义这一过程，并研究是否可以操纵它来治疗肝脏感染和其他疾病，如肿瘤。对相关途径和机制的透彻了解将使我们能够量身定做能够针对髓系来源的抑制细胞或逆转“饥饿”T细胞缺陷的治疗方法。这种方法将在实验室中使用从患者的血液和肝脏中提取的细胞、在特殊的3D肝脏培养系统中以及在新的乙肝病毒感染模型中进行测试。所有样本都是在完全知情同意和道德委员会批准的情况下采集的。只有在诊断或治疗所需的程序中剩余组织时，才会采集肝脏样本。我们的结果不仅有助于开发更好的乙肝和肝癌治疗方法，还将加深我们对肝脏如何抑制免疫反应的了解。因此，我们的发现可以应用于其他以肝脏为目标的感染的治疗，如疟疾，并反过来可以被利用来防止肝脏移植的排斥反应或治疗自身免疫性肝病。

Around one third of the world's population are estimated to have been exposed to hepatitis B virus (HBV) and at least 350 million people remain chronically infected. The resulting liver diseases include cirrhosis and liver cancer and are responsible for more than a million deaths every year. Existing therapies rarely achieve a cure. Patients are therefore consigned to long-term treatment, which remains unaffordable for many of the countries where the infection is most prevalent and carries risks of viral resistance and toxicity. Liver cancer is the third commonest cause of cancer-related deaths and treatments for it remain very limited. Our work is focused on understanding how to boost the body's natural immunity in order to achieve control of HBV and complications like liver cancer. We think that this should be achievable since many adults who get infected with HBV, naturally develop an immune response that controls it successfully for the rest of their lives. It is well known that T cells are critical for controlling viruses like HBV and that their numbers and function are drastically impaired in patients with chronic infection. We have found that one reason their T cells don't expand and work properly is that they are being starved of key nutrients like arginine. Our new findings reveal that another specialised immune cell type called "myeloid-derived suppressor cells" deprives T cells of nutrients and thereby stunts their responsiveness. These suppressor cells help to damp-down immune responses in the liver to stop them damaging this vital organ but in doing so, impair the control of pathogens like HBV. We now propose to define this process more comprehensively and investigate whether it can be manipulated to treat liver infections and other conditions such as tumours. A thorough understanding of the pathways and mechanisms involved will allow us to tailor therapies that can specifically target myeloid-derived suppressor cells or reverse the defects in "starved" T cells. This approach will be tested in the lab using cells extracted from the blood and liver of patients, in special 3D liver culture systems and in a new model of HBV infection. All samples are taken with fully informed consent and ethical board approval. Liver samples are only taken when there is surplus tissue left from procedures required for diagnosis or treatment.Our results will not only help with the development of better treatments for HBV and liver cancer, they will also enhance our understanding of how the liver suppresses immune responses. Our findings could therefore be applied to the treatment of other infections that target the liver like malaria and could conversely be harnessed to prevent rejection of liver transplants or to treat autoimmune liver disease.