Collectin-11 as a trigger of the innate immune response in renal transplantation

Collectin-11 作为肾移植中先天免疫反应的触发因素

• 批准号: MR/M012263/1
• 负责人: Steven Sacks
• 金额: $ 71.41万
• 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%2FM012263%2F1
• 关键词: Collectin; 11; trigger; innate; immune

When an organ is transplanted from one person to another, the disturbance of blood flow caused by the transplant procedure frequently results in inflammation. Substantial tissue damage can occur during the phase of oxygen deprivation and during the restoration of blood flow, when the kidney is exposed to harmful oxidants. The loss of healthy tissue and subsequent scarring may shorten the life of the transplant and of the patient. Complement is a set of inflammatory molecules, which we have found is easily activated during kidney transplantation. Activated complement can contribute greatly to renal transplant injury, as our past research has shown. Our current research has identified a possible trigger for this injury; originally called kidney collectin, this trigger was later renamed collectin type-11. Our exploratory studies have indicated that collectin-11 is released into kidneys after the flow of blood is interrupted. A series of biochemical steps initiated by collectin-11 then appears to halt the recovery of the transplanted organ. We need to work out how collectin-11 attaches to the cells of the kidney after release. We also need to find out how collectin-11 can transform the transplanted kidney into an inflamed organ by unleashing the complement system. It is vital to work out the detailed biochemical steps, so that we can learn how to protect the donor organ from collectin-11. What we learn from this study will help medical science to develop more accurate monitoring of the transplant - which most likely will involve a simple urine test. The findings will also help us to work out how to shield the donor organ before it is transplanted. We already have methods for coating the donor organ with protective therapies. This work can tell us if more effort should be directed towards blocking collectin-11. Given the shortage of donor organs and reliance on kidneys that have been removed after circulatory arrest, the urgency to protect these donor organs from blood-flow damage is very high. We depend on basic research to direct our efforts; here collectin-11 seems an important new target because of its proximity to the early pathway of events that trigger the inflammatory reaction. Potentially, treatment could prevent a substantial amount of damage and extend the life of the kidney transplant.

当器官从一个人移植到另一个人身上时，移植过程中引起的血液流动障碍经常会导致炎症。当肾脏暴露在有害的氧化剂中时，在缺氧期和血流恢复期间可能会发生实质性的组织损伤。健康组织的丧失和随之而来的疤痕可能会缩短移植和患者的寿命。补体是一组炎性分子，我们发现在肾移植过程中很容易被激活。正如我们过去的研究表明的那样，激活的补体可以极大地促进肾移植损伤。我们目前的研究已经确定了这种损伤的可能触发因素；最初被称为肾脏集合素，后来被重新命名为集合素-11。我们的探索性研究表明，在血液流动中断后，集合素-11会释放到肾脏中。然后，由胶原素-11启动的一系列生化步骤似乎会阻止移植器官的恢复。我们需要弄清楚在释放后，集合素-11是如何附着在肾脏细胞上的。我们还需要找出集合素-11如何通过释放补体系统将移植的肾脏转变为炎症器官。制定详细的生化步骤是至关重要的，这样我们才能了解如何保护捐赠者的器官免受集合素-11的影响。我们从这项研究中学到的东西将有助于医学科学开发更准确的移植监测--这很可能涉及简单的尿液测试。这些发现还将帮助我们研究如何在移植前保护捐赠者的器官。我们已经有了在捐献器官上涂上保护性疗法的方法。这项工作可以告诉我们，是否应该做出更多努力来阻断集合素-11。鉴于供体器官的短缺和对循环骤停后摘除的肾脏的依赖，保护这些供体器官免受血流损害的紧迫性非常高。我们依赖基础研究来指导我们的努力；在这里，集合素-11似乎是一个重要的新靶点，因为它接近触发炎症反应的事件的早期途径。潜在地，治疗可以防止大量损害并延长肾移植的寿命。

项目成果

Human stem cell-derived retinal epithelial cells activate complement via collectin 11 in response to stress.

• DOI: 10.1038/s41598-017-15212-z
• 发表时间: 2017-11-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Fanelli G;Gonzalez-Cordero A;Gardner PJ;Peng Q;Fernando M;Kloc M;Farrar CA;Naeem A;Garred P;Ali RR;Sacks SH
• 通讯作者: Sacks SH

Structural and functional diversity of collectins and ficolins and their relationship to disease.

• DOI: 10.1007/s00281-017-0642-0
• 发表时间: 2018-01
• 期刊: Seminars in immunopathology
• 影响因子: 9
• 作者: Howard M;Farrar CA;Sacks SH
• 通讯作者: Sacks SH

Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein-Associated Serine Protease 2.

解构实验性炎症性关节炎发病机理中的凝集素途径：凝集素纤维蛋白B和甘露糖结合蛋白相关的丝氨酸蛋白酶2的重要作用。

• DOI: 10.4049/jimmunol.1700119
• 发表时间: 2017-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Banda NK;Acharya S;Scheinman RI;Mehta G;Takahashi M;Endo Y;Zhou W;Farrar CA;Sacks SH;Fujita T;Sekine H;Holers VM
• 通讯作者: Holers VM

Fucose as a new therapeutic target in renal transplantation.

• DOI: 10.1007/s00467-020-04588-2
• 发表时间: 2021-05
• 期刊: Pediatric nephrology (Berlin, Germany)
• 作者: Howard MC;Nauser CL;Vizitiu DA;Sacks SH
• 通讯作者: Sacks SH