Localised inhibition of thrombin at endothelial surfaces - a translational strategy to inhibit immune responses to localised antigen

内皮表面凝血酶的局部抑制——抑制对局部抗原的免疫反应的转化策略

• 批准号: MR/P018513/1
• 金额: $ 44.3万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP018513%2F1
• 关键词: Localised; inhibition; thrombin; endothelial; surfaces

Innate immune mechanisms mediate multiple human inflammatory diseases and shape the way that adaptive immune responses (i.e. T and B cell-dependent responses) develop. Although therapeutics against innate effectors are becoming available, for instance agents targeting complement or specific cytokines, there is still a dearth of therapies that target inflammation per se, and corticosteroids, with multiple troublesome side effects, remain the mainstay of therapy for most inflammatory diseases. Movement of leukocytes along chemical gradients into underlying tissues underpins all inflammation. The chemicals involved are called 'chemokines'. The supervisors of this project have shown that an enzyme involved in blood clotting, called thrombin, is absolutely required to generate these chemokine gradients to initiate recruitment of cells at the beginning of inflammation. In this case, thrombin is acting through receptors expressed on the blood vessels at the site where inflammation is about to develop, rather than causing a blood clot to form. There are lots of drugs currently available to inhibit clotting, some of which inhibit the actions of thrombin. These drugs, called anticoagulants, are very effective at inhibiting inflammation in small and large animals. However, when tested in humans, they have been shown to cause significant problems related to bleeding, sometimes into the brain (causing strokes). Therefore, they are not routinely used to inhibit inflammation. The supervisors have invented a completely novel type of drug called Thrombalexin, that tethers to the cells lining a blood vessel and inhibits thrombin, but only at that site. It is therefore a good way to prevent clotting at specific sites, such as inside a transplanted organ. Based on promising preliminary data, Thrombalexin is undergoing rigorous testing and development that is required before it can be used as a drug. In the first clinical trial, which is planned for late 2017/early 2018, it will be perfused into a transplanted organ before being transplanted into recipients who are at high risk of clotting in the immediate post-transplant period. However, based on what we know about the role of thrombin in generating chemokines, Thrombalexin might have significant impact in inflammatory situations where clotting is not a problem, and by localising to specific sites, it might turn out to be a drug that can be used safely to inhibit localised inflammation. This is what my project will investigate.Because a transplanted organ undergoing rejection is a very good example of localised inflammation, I will predominantly (though not exclusively) use transplant models in my work, testing the ability of Thrombalexin to inhibit both aggressive and smouldering rejection, and showing that one of the main mechanisms by which it works is through inhibition of chemokine gradients and inhibition of cell recruitment into the transplant. Because my project will overlap with the phase 1 clinical trial of Thrombalexin in transplant patients, I will have an ideal opportunity to study whether Thrombalexin also inhibits chemokine secretion in humans, and ultimately to link this to changes in organ performance, cell recruitment and rejection-free survival.

先天免疫机制介导多种人类炎性疾病，并形成适应性免疫应答（即T和B细胞依赖性应答）发展的方式。尽管针对先天效应物的治疗剂变得可用，例如靶向补体或特异性细胞因子的药剂，但仍然缺乏靶向炎症本身的疗法，并且具有多种麻烦副作用的皮质类固醇仍然是大多数炎性疾病的主要疗法。白细胞沿着化学梯度运动到下层组织中是所有炎症的基础。所涉及的化学物质被称为“趋化因子”。该项目的主管已经表明，一种参与血液凝固的酶，称为凝血酶，绝对需要产生这些趋化因子梯度，以在炎症开始时启动细胞的募集。在这种情况下，凝血酶是通过在炎症即将发展的部位的血管上表达的受体起作用的，而不是导致血凝块形成。目前有许多药物可用于抑制凝血，其中一些抑制凝血酶的作用。这些药物称为抗凝剂，在抑制小型和大型动物的炎症方面非常有效。然而，当在人体中进行测试时，它们已被证明会导致与出血有关的重大问题，有时会进入大脑（导致中风）。因此，它们通常不用于抑制炎症。研究人员发明了一种全新的药物，名为血栓素，它可以与血管内壁的细胞结合，抑制凝血酶，但仅限于该部位。因此，这是防止特定部位（如移植器官内部）凝血的好方法。基于有希望的初步数据，血栓素正在接受严格的测试和开发，这是将其用作药物之前所需的。在计划于2017年底/2018年初进行的第一项临床试验中，它将被灌注到移植器官中，然后移植到移植后即刻凝血风险高的受体中。然而，根据我们对凝血酶在产生趋化因子中的作用的了解，血栓素可能在凝血不成问题的炎症情况下产生重大影响，并且通过定位于特定部位，它可能成为一种可以安全地用于抑制局部炎症的药物。这就是我的项目要研究的。因为移植器官发生排斥反应是局部炎症的一个很好的例子，我将主要在我的工作中使用移植模型，测试血栓素抑制侵袭性和郁积性排斥反应的能力，并表明其主要作用机制之一是通过抑制趋化因子梯度和抑制细胞募集到移植因为我的项目将与Thrombalexin在移植患者中的1期临床试验重叠，我将有一个理想的机会来研究Thrombalexin是否也抑制人类趋化因子的分泌，并最终将其与器官性能，细胞募集和无排斥生存的变化联系起来。

项目成果

Regression of Atherosclerosis in ApoE-/- Mice Via Modulation of Monocyte Recruitment and Phenotype, Induced by Weekly Dosing of a Novel "Cytotopic" Anti-Thrombin Without Prolonged Anticoagulation.

通过调节单核细胞募集和表型诱导载脂蛋白E-/-小鼠动脉粥样硬化的消退，每周服用新型 "细胞异位 "抗凝血酶而无需长期抗凝。

• DOI: 10.1161/jaha.119.014811
• 发表时间: 2020-07-07
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Chen D;Li K;Festenstein S;Karegli J;Wilkinson H;Leonard H;Wei LL;Ma N;Xia M;Tam H;Wang JA;Xu Q;McVey JH;Smith RAG;Dorling A
• 通讯作者: Dorling A