Pathfinder: An experimental medicine study of the 18 kD translocator protein as a novel neuroimmunodulatory target for multiple sclerosis

多发性硬化症(MS)是由血液中循环的淋巴细胞、来自另一组血细胞的巨噬细胞和小胶质细胞引起的脑部炎症，小胶质细胞是大脑自身驻留的炎症细胞。尽管到目前为止开发的治疗方法侧重于更好地控制淋巴细胞活性，但小胶质细胞(和巨噬细胞，它们具有小胶质细胞的一些关键特征)在与复发相关的炎症中也发挥着重要作用。它们也可能在推动与进行性疾病相关的神经退化方面发挥重要作用。例如，我们的团队发现，在大脑中小胶质细胞激活水平较高的人中，继发性进行性多发性硬化症的残疾程度更高。然而，激活的小胶质细胞并不直接受到目前批准的治疗MS的药物的调节。“18kD翻译蛋白”或“TSPO”是一种在小胶质细胞和巨噬细胞中丰富表达的天然分子。许多科学家使用培养皿中的细胞或疾病的动物模型进行的研究表明，与TSPO结合的化学物质(例如，一些与常见的抗焦虑药物如安定有关)可以减少炎症。这表明，TSPO可能提供了一种新的方式来调节与MS相关的炎症，并且由于开发的与TSPO相互作用的分子都可以穿透大脑，对小胶质细胞有独特的作用。这种可能性从未在人类研究中得到测试。为了解决这一问题，我们提议在人类和人类细胞或组织中进行一系列全面的实验，旨在评估TSPO作为治疗多发性硬化症患者的新的免疫调节靶点。我们专注于继发性进展性多发性硬化症，因为它是一种严重的进行性多发性硬化症，与高水平的大脑小胶质细胞激活有关，目前批准的药物无法很好地治疗它。我们的研究将涉及对脑组织的研究(由多发性硬化症患者捐赠给多发性硬化症协会脑库)，以了解小胶质细胞中TSPO是否增加，这些小胶质细胞正在产生破坏神经细胞和髓鞘的化学信号。我们将研究培养皿中生长的人小胶质细胞在用调节TSPO功能的分子处理时的炎症反应。最后，在非常谨慎的控制条件下，我们将每天给健康志愿者和多发性硬化症患者服用安全的TSPO结合分子XBD173，为期一周，以了解服用这种分子是否真的可以改变免疫反应。将使用多种方法测量血液和大脑中的炎症。相对较新的磁共振成像(MRI)和正电子发射断层扫描(PET)脑扫描方法将进一步验证这一应用，然后作为健康志愿者和多发性硬化症患者的额外工具，更直接地提供有关脑部炎症的影响的信息。我们的跨学科临床研究将汇集多发性硬化症药物开发、神经免疫学和神经成像方面的广泛专家。它将首次测试TSPO结合分子可以调节人类小胶质细胞的炎症反应的假设，帮助我们发现如何监测这些分子可能产生的任何影响，并开始告诉我们它们是如何工作的。我们不认为XBD173本身可以用于治疗，但已经开发出许多其他分子，应该以类似的方式发挥作用。如果我们的研究成功，我们打算选择并进一步开发这些分子中的一个，作为潜在的与更传统的多发性硬化症药物的联合治疗。一种调节小胶质细胞的分子和目前批准的对淋巴细胞有重大影响的疾病修饰药物之一，可以提供一种更有效的方法，不仅治疗复发，而且治疗进行性多发性硬化。

Multiple sclerosis (MS) involves inflammation in the brain caused by lymphocytes that that circulate in the blood, by macrophages derived from another set of blood cells and by microglia, which are the brain's own resident inflammatory cells. Although treatments developed to date have focused on better controlling lymphocyte activity, microglia (and macrophages, which share some key features of microglia) also play a major role in the inflammation associated with relapses. They also may be important in driving the neurodegeneration associated with progressive forms of the disease. Our group has discovered, for example, that disability in secondary progressive MS is greater in people with higher levels of microglial activation in the brain. However, activated microglia are not directly modulated by current approved medicines for MS. The "18kD Translator Protein" or "TSPO" is a natural molecule richly expressed in microglia and macrophages. Studies by many scientists using cells in a dish or animal models of diseases suggest that chemicals (e.g., some related to common anti-anxiety drugs like valium) binding to TSPO reduce inflammation. This suggests that TSPO may provide a new way of modulating inflammation associated with MS and, as molecules developed to interact with TSPO all can penetrate the brain, have a unique action on microglia. This possibility has never been tested in human studies.To address this, we are proposing a comprehensive series of experiments in humans and with human cells or tissue that are intended to evaluate TSPO as a novel immune modulatory target for treatment of people with MS. We are focusing on secondary progressive MS because it is a serious, progressive form of the disease associated with high levels of brain microglial activation that cannot be well treated with current approved medicines. Our study will involve studies of brain tissue (donated to the MS Society Brain Bank by people with MS) to see whether TSPO is increased in microglia that are producing the kinds of chemical signals that damage nerve cells and myelin. We will study the inflammatory responses of human microglia grown in a dish when they are treated with molecules that modulate TSPO functions. Finally, under very carefully controlled conditions, we will administer the safe TSPO binding molecule XBD173 to healthy volunteers and to people with MS daily for a week to understand whether immune responses really can be changed with administration of this kind of molecule. Multiple measures of inflammation in the blood and in the brain will be used. Relatively new magnetic resonance imaging (MRI) and positron emission tomography (PET) brain scanning methods will be further validated for this application and then used as an additional tool in the healthy volunteers and people with MS to provide information more directly about the effects on brain inflammation.Our interdisciplinary clinical study will bring together a broad range of experts in drug development for MS, neuroimmunology and neuroimaging. It will provide a first test of the hypothesis that a TSPO binding molecule can modulate the inflammatory responses of microglia in humans, help us to discover how to monitor any effects that such molecules might be having and begin to tell us how they work. We do not believe that XBD173 itself can be used as a treatment, but many other molecules have been developed that should work in a similar way. If our study is successful, we intend to select and further develop one of these other molecules for use as a potential combination treatment with more traditional MS drugs. Together, a molecule modulating microglia and one of the currently approved disease modifying drugs that has a major effect on lymphocytes could provide a more powerful way of treating not just relapses, but also the progressive forms of MS.