Using mesenchymal stromal cell secretory products to improve human islet transplantation.
使用间充质基质细胞分泌产品改善人类胰岛移植。
基本信息
- 批准号:MR/W030004/1
- 负责人:
- 金额:$ 39.65万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2023
- 资助国家:英国
- 起止时间:2023 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Islet transplantation offers the prospect of a cure for type 1 diabetes (T1D) rather than merely treating the symptoms with insulin, which should bring major benefits in reducing the secondary complications associated with T1D. Islet transplantation is currently reserved as a treatment for a subgroup of patients with T1D who fail to improve their hypoglycaemia despite state-of-the-art medical therapy. A major problem with islet transplantation as a treatment is the significant loss of transplanted cells (up to 80%) which occurs in the 24-48 hours immediately after transplantation. This loss of function is partly because the isolated islets in the graft are fragile and easily damaged, and partly because the graft environment, inside the liver bloodstream, reacts to the graft by causing inflammation which irreversibly damages the islets. As a result, insulin independence is only achieved long-term in 17% of UK's islet cell transplant recipients. In animal studies, co-transplanting "helper" cells known as mesenchymal stromal cells (MSCs) with islets improves graft function and survival, and suppresses inflammation, but this is not technically feasible in clinical human islet transplants. KCL islet biology group has experimental evidence from studies using mouse models of islet isolation, treatment and transplantation suggesting that many of the beneficial effects of MSCs can be attributed to biologically active molecules which they secrete and that the benefits can be replicated merely by supplying the molecules to the islets before transplantation. I will now investigate how to use such molecules to improve islet graft survival and function in -cell-free" system, with the aim of using this information to improve outcomes of clinical protocols for human islet transplantation. This project will demonstrate the translational potential of this approach by assessing whether pre-treatment of isolated human islets with MSC-derived molecules is able to protect them during the period immediately after transplantation, to improve the long-term chances of graft survival and function. I will assess human islet function and survival under experimental conditions designed to mimic the post-transplantation environment and use this information to inform a study in a recently developed mouse model of human islet transplantation. During these studies I will also investigate new blood tests or biomarkers that could tell us how well the islet cells are functioning in transplant recipients. In parallel, I will liaise with the UK Islet Transplantation Consortium (UKITC), the clinical consortium of human islet transplantation centres within the UK, to design a first-in-man clinical study to assess the benefits of pre-treating human islets with MSC-derived molecules before transplantation. Our collaboration with the UKITC, which has an established infrastructure for conducting research and delivering pioneering work in islet cell transplantation, will ensure the fastest route to translation of our experimental studies to improve the outcomes of this treatment. This project will therefore inform how best to design "cell-free" treatments of human islets prior to transplantation to improve the functional survival of the islet graft, particularly within the first few days after transplantation, and so improve the clinical outcomes for individual islet transplant recipients.
胰岛移植提供了治愈1型糖尿病(T1D)的前景,而不仅仅是用胰岛素治疗症状,这应该会在减少与T1D相关的继发性并发症方面带来重大好处。胰岛移植目前作为治疗T1D患者的一种方法,尽管有最先进的药物治疗,但他们的低血糖仍未得到改善。胰岛移植作为一种治疗方法的一个主要问题是移植细胞的显著损失(高达80%),发生在移植后24-48小时内。这种功能丧失的部分原因是移植物中孤立的胰岛很脆弱,很容易受损,部分原因是移植物的环境,在肝脏血流中,通过引起炎症来对移植物做出反应,从而不可逆转地损害胰岛。因此,在英国的胰岛细胞移植受者中,只有17%的人实现了长期的胰岛素独立。在动物研究中,将被称为间充质基质细胞(MSCs)的辅助细胞与胰岛联合移植可以改善移植物功能和存活率,并抑制炎症,但在临床人类胰岛移植中,这在技术上是不可行的。KCL胰岛生物学研究小组从使用小鼠胰岛分离、治疗和移植模型的研究中获得的实验证据表明,MSCs的许多有益作用可以归因于它们分泌的生物活性分子,并且只需在移植前向胰岛提供分子就可以复制这些好处。我现在将研究如何使用这些分子来提高胰岛移植物的存活率和功能,以期利用这些信息来改善人类胰岛移植的临床方案的结果。该项目将通过评估用间充质干细胞衍生的分子对分离的人胰岛进行预处理是否能够在移植后立即保护它们,以改善移植物存活和功能的长期机会,来展示这种方法的翻译潜力。我将在模拟移植后环境的实验条件下评估人类胰岛的功能和存活率,并利用这些信息为最近开发的人类胰岛移植小鼠模型的研究提供信息。在这些研究期间,我还将调查新的血液测试或生物标记物,它们可以告诉我们移植受者胰岛细胞的功能如何。同时,我将与英国人胰岛移植中心的临床联盟英国胰岛移植联合会(UKITC)联系,设计一项首个人的临床研究,以评估在移植前用MSC衍生分子预处理人的胰岛的好处。我们与英国国际贸易中心的合作将确保以最快的途径将我们的实验研究转化为改善这种治疗结果的方法。英国国际贸易中心拥有进行胰岛细胞移植研究和开展开创性工作的基础设施。因此,该项目将介绍如何在移植前最好地设计人胰岛的无细胞治疗,以提高胰岛移植物的功能存活率,特别是在移植后的头几天,从而改善个别胰岛移植受者的临床结果。
项目成果
期刊论文数量(0)
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Sufyan Hussain其他文献
Closed-loop systems: a bridge to cell therapy for type 1 diabetes?
闭环系统:通往 1 型糖尿病细胞疗法的桥梁?
- DOI:
10.1016/s2213-8587(24)00240-7 - 发表时间:
2024-11-01 - 期刊:
- 影响因子:41.800
- 作者:
Sufyan Hussain;Katarina Braune;Shareen Forbes;Peter A Senior - 通讯作者:
Peter A Senior
Influenza vaccination: a cross-sectional prospective audit of influenza vaccination in patients admitted to a London hospital
- DOI:
10.7861/clinmedicine.9-5-506 - 发表时间:
2009-10-01 - 期刊:
- 影响因子:3.2
- 作者:
Katherine Styles;Anshul Rastogi;Sufyan Hussain;Sonya Abraham - 通讯作者:
Sonya Abraham
Case series of using automated insulin delivery to improve glycaemic control in people with type 1 diabetes and end stage kidney disease on haemodialysis
- DOI:
10.1016/j.diabres.2024.111800 - 发表时间:
2024-11-01 - 期刊:
- 影响因子:
- 作者:
Khuram Chaudhry;Rebecca Hyslop;Thomas Johnston;Siobhan Pender;Sufyan Hussain;Janaka Karalliedde - 通讯作者:
Janaka Karalliedde
Sufyan Hussain的其他文献
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