T-bet as a master regulator of mucosal immunity and inflammatory bowel disease.

T-bet 作为粘膜免疫和炎症性肠病的主要调节剂。

• 批准号: MR/M003493/1
• 负责人: Graham Lord
• 金额: $ 158.64万
• 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: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM003493%2F1
• 关键词: bet; master; regulator; mucosal; immunity

Inflammatory bowel disease (IBD) affects 240,000 people in the UK and costs the NHS £700 million every year. It causes disabling symptoms, impaired quality of life and serious complications including cancer, bowel blockage and bowel perforation. Many patients will be hospitalised and some will need to undergo disfiguring operations. Unfortunately, it preferentially affects young, economically active patients whom live with this difficult disease for life. IBD patients lose more working days and are more likely to be unemployed than unaffected people and its incidence appears to be increasing. At present, even the best treatment strategies fail to keep the disease in check for long periods of time. It is thought that IBD is caused by inappropriate activation of the intestinal immune system, which triggers chronic inflammation of the gut. It is now appreciated that certain immune cells play an instrumental role initiating and propagating this detrimental inflammatory process in IBD. In recent years there have been considerable advances made in our understanding of which immune cell types and which immune molecules are likely to play important roles in the disease process. It is hoped that in the coming years that insights into the regulation of gut immune cells can be harnessed to inform the development of better treatments.This proposal aims to determine whether the immune abnormalities associated with IBD can be specifically targeted to prevent the disease. It focuses on a type of molecule known as a transcription factor, which is a very important regulator of the immune responses seen in the gut of IBD patients.One of these molecules, (T-bet) stands out as a potentially important regulator of gut immune cells. It is abnormally expressed in IBD patients and in mice developing gut inflammation that resembles IBD. It is predicted to control many different immune mechanisms, including some of those thought to be important in IBD causation. T-bet is only found in immune cells and other bone marrow derived cells. It is therefore anticipated that modulating its action in patients is unlikely to cause unanticipated side effects in other organs of the body.By comparing normal mice with mice lacking T-bet in certain immune cell types we will determine how this particular molecule affects immune specific mechanisms in the gut and influences IBD susceptibility. We will also try to identify novel targets for therapies that are designed to selectively suppress affect the type of cells causing IBD. This will provide insight as to whether targeting T-bet is likely to reverse inflammation in IBD, a highly desirable goal for patients with this disabling disease.This research will be conducted at King's College London by scientists and doctors with proven track records in IBD research. In addition, close collaborations have been formed with other expert researchers at Queen Mary University of London, University College London and the University of Manchester in order to maximise expertise.

炎症性肠病(IBD)影响着英国24万人，每年给NHS造成7亿英镑的损失。它会导致致残症状、生活质量下降和严重并发症，包括癌症、肠梗阻和肠穿孔。许多患者将被送往医院，一些患者将需要接受毁容手术。不幸的是，它优先影响年轻的、经济活跃的患者，他们终生患有这种困难的疾病。与未受影响的人相比，IBD患者损失的工作日更多，失业的可能性更大，而且其发病率似乎正在增加。目前，即使是最好的治疗策略也无法在很长一段时间内控制住疾病。据认为，IBD是由肠道免疫系统的不适当激活引起的，后者触发了肠道的慢性炎症。现在人们认识到，某些免疫细胞在IBD中起着启动和传播这一有害炎症过程的重要作用。近年来，我们在了解哪些免疫细胞类型和哪些免疫分子可能在疾病过程中发挥重要作用方面取得了相当大的进展。希望在接下来的几年里，能够利用对肠道免疫细胞调控的见解来为更好的治疗方法的开发提供信息。这项建议旨在确定与IBD相关的免疫异常是否可以被特定地靶向预防该疾病。它专注于一种被称为转录因子的分子，它是IBD患者肠道免疫反应的一种非常重要的调节因子。其中一种分子，T-bet，是肠道免疫细胞的潜在重要调节因子。它在IBD患者和发展为类似IBD的肠道炎症的小鼠中异常表达。据预测，它可以控制许多不同的免疫机制，包括一些被认为在IBD病因中起重要作用的免疫机制。T-bet只存在于免疫细胞和其他骨髓来源的细胞中。因此，预计调节T-bet在患者体内的作用不太可能在身体的其他器官引起意想不到的副作用。通过比较正常小鼠和某些免疫细胞类型缺乏T-bet的小鼠，我们将确定这种特定的分子如何影响肠道中的免疫特异性机制，并影响IBD的易感性。我们还将尝试为治疗确定新的靶点，这些治疗旨在选择性地抑制导致IBD的细胞类型。这将提供关于靶向T-bet是否可能逆转IBD炎症的洞察，这对患有这种致残疾病的患者来说是一个非常可取的目标。这项研究将由在IBD研究方面有可靠记录的科学家和医生在伦敦国王学院进行。此外，还与伦敦玛丽女王大学、伦敦大学学院和曼彻斯特大学的其他专家研究人员密切合作，以最大限度地发挥专业知识的作用。

项目成果

Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease.

• DOI: 10.1136/gutjnl-2014-306919
• 发表时间: 2016-04
• 期刊: Gut
• 影响因子: 24.5
• 作者: Canavan JB;Scottà C;Vossenkämper A;Goldberg R;Elder MJ;Shoval I;Marks E;Stolarczyk E;Lo JW;Powell N;Fazekasova H;Irving PM;Sanderson JD;Howard JK;Yagel S;Afzali B;MacDonald TT;Hernandez-Fuentes MP;Shpigel NY;Lombardi G;Lord GM
• 通讯作者: Lord GM

Reply.

回复。

• DOI: 10.1002/art.40923
• 发表时间: 2019
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Kim,AlfredHJ;Strand,Vibeke;Atkinson,JohnP
• 通讯作者: Atkinson,JohnP

The Th1 cell regulatory circuitry is largely conserved between human and mouse.

• DOI: 10.26508/lsa.202101075
• 发表时间: 2021-11
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Henderson S;Pullabhatla V;Hertweck A;de Rinaldis E;Herrero J;Lord GM;Jenner RG
• 通讯作者: Jenner RG

Role of retinoic acid in the stability of the T-helper-type 1 lineage and implications for autoimmunity.

视黄酸在 T 辅助细胞 1 型谱系稳定性中的作用及其对自身免疫的影响。

• DOI: 10.1016/s0140-6736(15)60340-3
• 发表时间: 2015
• 期刊: Lancet (London, England)
• 作者: Brown C

T-bet controls intestinal mucosa immune responses via repression of type 2 innate lymphoid cell function.

• DOI: 10.1038/s41385-018-0092-6
• 发表时间: 2019-01
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Garrido-Mesa N;Schroeder JH;Stolarczyk E;Gallagher AL;Lo JW;Bailey C;Campbell L;Sexl V;MacDonald TT;Howard JK;Grencis RK;Powell N;Lord GM
• 通讯作者: Lord GM