Overcoming immunological barriers to regenerative medicine

克服再生医学的免疫障碍

• 批准号: MR/L022699/1
• 负责人: Fiona Watt
• 金额: $ 308.64万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL022699%2F1
• 关键词: Overcoming; immunological; barriers; regenerative; medicine

The goal of the field of regenerative medicine is to replace damaged or diseased tissue and thereby find cures for diseases that are currently untreatable. At present two different approaches appear feasible: one is to stimulate the body's own cells to repair the tissue and the other is to transplant new cells into the body. In the case of cell transplantation one could transplant cells from one individual to another (allogeneic cells), as happens routinely in blood donation. Alternatively, one could isolate a small number of a patient's own skin or blood cells and convert them in the lab into cells called pluripotent stem cells that can then form any tissue in the body, so that patients can be treated with their own cells. No matter which strategy is taken, it is essential to overcome the body's natural immune defences in order for the treatment to succeed. In the case of allogeneic cells, the body recognises that the cells as foreign and kills them - the reason why this is not a problem in blood donation is that there are so many donors in the population that good matches for different individuals can be found. Even when the potential treatment involves the patient's own cells, the immune system can be provoked in response to tissue damage, resulting in inflammation whereby immune cells of the body respond to danger signals and engulf the transplanted cells.We have assembled a team of researchers from different backgrounds to collaborate in order to find new ways to control the immune system to make regenerative medicine treatments more effective. Our team includes researchers with many years' experience in organ transplantation, who are developing ways of reducing the need for immunosuppressive drugs, and researchers who are already carrying out clinical trials of cell transplantation to cure certain forms of blindness and liver failure. We also have experts who are comparing whether cell transplantation or endogenous repair are better approaches for treating heart failure, experts in immunology, pluripotent stem cells and cells from adult tissues. We have set out to answer three questions that are of central importance in regenerative medicine. We want to identify the proteins that transplanted cells secrete to communicate with the immune system and discover whether different cell types produce different signals. It might be that liver cells produce different signals to eye cells, or that liver cells produce different signals if they have come from an adult rather than a pluripotent stem cell. This information will help us decide whether cells from one source might be better for transplantation than those from another source, and will also give us clues about the best ways to protect the cells from immune attack. The next question is whether the signals we identify as potentially contributing to transplant failure can be blocked, for example by coating cells with a protein that protects them from attack or by transplanting back immune cells generated from pluripotent stem cells. The final question is how inflammation contributes to endogenous repair and influences the fate of transplanted cells. We will identify different types of inflammatory cell and then examine whether destroying each cell type improves or worsens tissue repair.Our research will lead eventually to improved treatments for blindness, heart failure, liver failure and inflammatory bowel disease. Our discoveries will be shared with other researchers, so that they can apply our observations, experimental skills and tools to other important diseases. We believe that collaborations amongst researchers with very different perspectives offer the best opportunity to harness the body's immune system to make treatments more effective.

再生医学领域的目标是替换受损或患病的组织，从而找到目前无法治疗的疾病的治疗方法。目前，两种不同的方法似乎是可行的：一种是刺激人体自身的细胞来修复组织，另一种是将新的细胞移植到体内。在细胞移植的情况下，可以将细胞从一个个体移植到另一个个体（同种异体细胞），就像献血中常规发生的那样。或者，人们可以分离出少量患者自己的皮肤或血细胞，并在实验室中将它们转化为称为多能干细胞的细胞，然后可以形成体内的任何组织，这样患者就可以用自己的细胞进行治疗。无论采取哪种策略，都必须克服身体的天然免疫防御，才能使治疗成功。在同种异体细胞的情况下，身体会识别出这些细胞是外来的，并杀死它们--这在献血中不是问题的原因是，人群中有如此多的献血者，可以为不同的个体找到良好的匹配。即使潜在的治疗涉及患者自己的细胞，免疫系统也会对组织损伤做出反应，我们召集了一个来自不同背景的研究人员团队进行合作，以寻找控制免疫系统的新方法，使再生医学治疗更有效。我们的团队包括在器官移植方面有多年经验的研究人员，他们正在开发减少免疫抑制药物需求的方法，以及已经进行细胞移植临床试验以治愈某些形式的失明和肝功能衰竭的研究人员。我们也有专家正在比较细胞移植或内源性修复是否是治疗心力衰竭的更好方法，免疫学专家，多能干细胞和成人组织细胞。我们已经着手回答再生医学中至关重要的三个问题。我们希望确定移植细胞分泌的与免疫系统沟通的蛋白质，并发现不同类型的细胞是否产生不同的信号。这可能是因为肝细胞产生的信号与眼细胞不同，或者如果肝细胞来自成年人而不是多能干细胞，则会产生不同的信号。这些信息将帮助我们决定来自一种来源的细胞是否比来自另一种来源的细胞更适合移植，并且还将为我们提供有关保护细胞免受免疫攻击的最佳方法的线索。下一个问题是，我们确定的可能导致移植失败的信号是否可以被阻断，例如通过用蛋白质包裹细胞以保护它们免受攻击，或者通过将多能干细胞产生的免疫细胞移植回来。最后一个问题是炎症如何促进内源性修复并影响移植细胞的命运。我们将识别不同类型的炎症细胞，然后检查破坏每种细胞类型是否会改善或破坏组织修复。我们的研究最终将导致失明，心力衰竭，肝功能衰竭和炎症性肠病的治疗方法得到改善。我们的发现将与其他研究人员分享，以便他们可以将我们的观察，实验技能和工具应用于其他重要疾病。我们相信，具有非常不同观点的研究人员之间的合作提供了利用人体免疫系统使治疗更有效的最佳机会。

项目成果

What Is Direct Allorecognition?

• DOI: 10.1007/s40472-016-0115-8
• 发表时间: 2016
• 期刊: Current transplantation reports
• 影响因子: 2.1

AAV-mediated liver-directed gene therapy for Acute Intermittent Porphyria: It is safe but is it effective?

AAV 介导的肝脏定向基因治疗急性间歇性卟啉症：安全但有效吗？

• DOI: 10.1016/j.jhep.2016.07.006
• 发表时间: 2016
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Brunetti-Pierri N

Galectin-1 is required for the regulatory function of B cells.

• DOI: 10.1038/s41598-018-19965-z
• 发表时间: 2018-02-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Alhabbab R;Blair P;Smyth LA;Ratnasothy K;Peng Q;Moreau A;Lechler R;Elgueta R;Lombardi G
• 通讯作者: Lombardi G

A blueprint for translational regenerative medicine.

• DOI: 10.1126/scitranslmed.aaz2253
• 发表时间: 2020-12-02
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Armstrong JPK;Keane TJ;Roques AC;Patrick PS;Mooney CM;Kuan WL;Pisupati V;Oreffo ROC;Stuckey DJ;Watt FM;Forbes SJ;Barker RA;Stevens MM
• 通讯作者: Stevens MM