Persistent Fatigue Induced by Interferon-alpha: A New Immunological Model for Chronic Fatigue Syndrome

干扰素-α诱导的持续性疲劳：慢性疲劳综合征的新免疫学模型

• 批准号: MR/J002739/1
• 负责人: Carmine M. Pariante
• 金额: $ 47.54万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ002739%2F1
• 关键词: Persistent; Fatigue; Induced; Interferon; alpha

Chronic fatigue syndrome (CFS) is a medical condition in which patients feel persistently and overwhelmingly tired and run down, both physically and mentally. In addition, they have difficulty with concentration, flu-like symptoms and aches and pains. This condition interferes with daily life activity, and, in some patients, is profoundly disabling. Although many years of research have been conduced on CFS, we still do not know what is causing it. One biological system that is involved in CFS is the "immune system", that is, the system dedicated to fight infections in our body. Indeed, in many cases CFS is triggered by an infection, but then the symptoms continue even after the infection has been eliminated. Specifically, infections are always accompanied by acute fatigue and flu-like symptoms, as a consequence of the infection-driven immune activation; however, in patients with CFS the immune activation and the associated fatigue and flu-like symptoms persist for months or years. Moreover, there is evidence that the immune system is in a state of "hyper-activity" in patients with CFS, as if they were fighting an infective agent, even though they do not have an ongoing infection. This project aims to understand exactly this process: how the infection and the acute immune activation evolve into CFS, and what are the risk factors that make this process occur in some individuals but not others. Clearly, trying to study this process in subjects experiencing naturally-acquired infections is very difficult, for the unpredictability of these events. In contrast, we want to model the development of CFS by studying a group of patients that have a pre-existing infection (chronic viral hepatitis C, HCV) and that receive a course of treatment (lasting months) with the immune activator, interferon-alpha (IFN-alpha). IFN-alpha is the treatment of choice for HCV infection. Because it activates the immune system, IFN-alpha also induces fatigue and flu-like symptoms in all patients. Moreover, and of particular relevance for this study, a considerable proportion of patients continue to experience debilitating persistent fatigue, and other symptoms that are similar to CFS, for 6 months or even one year after the cessation of IFN-alpha. This phenomenon strikingly resembles CFS, which, as mentioned above, also persists after the infective/immune trigger has been eliminated. Therefore, we are proposing to use IFN-alpha as a model to understand how an immune trigger induces persistent fatigue even when the initial immune trigger is no longer present. To do this, we will assess these patients throughout the many months of IFN-alpha treatment and at 6 months after cessation of treatment, in order to identify those with persistent "post-IFN-alpha-treatment" fatigue, and understand what biological and clinical changes lead to this outcome. Moreover, we will compare these patients with a group of patients with CFS and with a group of healthy individuals, conducting the same biological and clinical assessment. We will measure changes occurring in blood hormones that are relevant to the immune function, such as "cytokines" and "cortisol". In addition, we will asses changes in measures of well-being, including physical fitness, concentration, sleep and mood. We are confident that creating and validating this model of CFS will generate a host of future studies aimed at improving the health of people with CFS. For example, we will be able to build a check-list of blood measures that could predict who will, and who will not, develop CFS; we will test novel treatments for "post-IFN-alpha-treatment" fatigue, facilitated by the fact that these patients are homogeneous in their clinical background, and then extend these treatments to patients with CFS; and, finally, we will truly understand what happens in the body during the development of CFS, and thus identify novel therapeutic approaches to interrupt this development.

慢性疲劳综合征（CFS）是一种医学疾病，患者在身体和精神上都感到持续和压倒性的疲劳和疲惫。此外，他们难以集中注意力，出现流感样症状和疼痛。这种情况会干扰日常生活活动，并且在某些患者中会严重致残。虽然对CFS进行了多年的研究，但我们仍然不知道是什么引起了CFS。其中一个涉及CFS的生物系统是“免疫系统”，即专门用于对抗我们体内感染的系统。事实上，在许多情况下，CFS是由感染引发的，但即使在感染消除后，症状仍在继续。具体来说，感染总是伴随着急性疲劳和流感样症状，这是感染驱动的免疫激活的结果;然而，在CFS患者中，免疫激活和相关的疲劳和流感样症状持续数月或数年。此外，有证据表明，CFS患者的免疫系统处于“过度活跃”状态，就好像他们正在与感染因子作斗争，即使他们没有持续的感染。该项目旨在准确了解这一过程：感染和急性免疫激活如何演变为CFS，以及哪些风险因素使这一过程发生在某些人身上，而不是其他人。显然，由于这些事件的不可预测性，试图在经历自然获得性感染的受试者中研究这一过程是非常困难的。相比之下，我们希望通过研究一组预先存在感染（慢性病毒性丙型肝炎，HCV）并接受免疫激活剂干扰素-α（IFN-α）治疗（持续数月）的患者来模拟CFS的发展。IFN-α是治疗HCV感染的首选。因为它激活免疫系统，IFN-α也会引起所有患者的疲劳和流感样症状。此外，与本研究特别相关的是，相当大比例的患者在停止IFN-α后6个月甚至1年内继续经历使人衰弱的持续疲劳和类似于CFS的其他症状。这种现象与CFS非常相似，如上所述，CFS在感染/免疫触发因素消除后仍然存在。因此，我们建议使用IFN-α作为模型来了解免疫触发剂如何诱导持续性疲劳，即使最初的免疫触发剂不再存在。为了做到这一点，我们将在IFN-α治疗的几个月内和停止治疗后6个月对这些患者进行评估，以确定那些持续的“IFN-α治疗后”疲劳的患者，并了解导致这种结果的生物学和临床变化。此外，我们将这些患者与一组CFS患者和一组健康个体进行比较，进行相同的生物学和临床评估。我们将测量与免疫功能相关的血液激素发生的变化，如“细胞因子”和“皮质醇”。此外，我们还将评估健康指标的变化，包括身体健康、注意力集中、睡眠和情绪。我们相信，创建和验证这种CFS模型将产生一系列旨在改善CFS患者健康的未来研究。例如，我们将能够建立一个血液指标的检查表，可以预测谁会，谁不会，发展CFS;我们将测试新的治疗“后IFN-α治疗”疲劳，这有助于这些患者在其临床背景的同质性，然后将这些治疗扩展到CFS患者;最后，我们将真正了解CFS发展过程中体内发生了什么，从而确定新的治疗方法来中断这种发展。

项目成果

Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis.

• DOI: 10.3389/fpsyt.2014.00084
• 发表时间: 2014
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Ajnakina O;Borges S;Di Forti M;Patel Y;Xu X;Green P;Stilo SA;Kolliakou A;Sood P;Marques TR;David AS;Prata D;Dazzan P;Powell J;Pariante C;Mondelli V;Morgan C;Murray RM;Fisher HL;Iyegbe C
• 通讯作者: Iyegbe C

Citizen, interrupted: the 2011 English riots from a psychosocial perspective.

公民，打断：从社会心理角度看 2011 年英国骚乱。

• DOI: 10.1017/s2045796012000364
• 发表时间: 2013
• 期刊: Epidemiology and psychiatric sciences
• 影响因子: 8.1
• 作者: Aiello G

Is there a link between childhood trauma, cognition, and amygdala and hippocampus volume in first-episode psychosis?

• DOI: 10.1016/j.schres.2012.01.035
• 发表时间: 2012-05-01
• 期刊: SCHIZOPHRENIA RESEARCH
• 影响因子: 4.5
• 作者: Aas, Monica;Navari, Serena;Dazzan, Paola
• 通讯作者: Dazzan, Paola

A systematic review of cognitive function in first-episode psychosis, including a discussion on childhood trauma, stress, and inflammation.

• DOI: 10.3389/fpsyt.2013.00182
• 发表时间: 2014-01-08
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Aas M;Dazzan P;Mondelli V;Melle I;Murray RM;Pariante CM
• 通讯作者: Pariante CM

Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis.

• DOI: 10.1038/npp.2012.253
• 发表时间: 2013-04
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology