Using minimal Factor H therapy and normothermic conditions to prepare kidneys for transplantation

使用最小 H 因子疗法和常温条件为肾脏移植做好准备

• 批准号: MR/T031867/1
• 负责人: Kevin Marchbank
• 金额: $ 92.97万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT031867%2F1
• 关键词: Using; minimal; Factor; therapy; normothermic

Kidney transplant is the gold-standard treatment for patients with renal failure. However, the supply of organs is limited in number and quality. This has necessitated the transplantation of kidneys from donation after the donors death or from non-optimal donors that are associated with increased risks. These kidneys are associated with prolonged times without adequate oxygen supply and increased cellular damage resulting in increased organ injury immediately after transplant. This can shorten the long-term survival of the kidney and result in patients requiring another transplant, compounding the organ shortage crisis.We have developed a novel anti-complement therapy based on a blood defence protein called factor H and one of its related proteins. Our drug is called HDM-FH (homodimeric minimal factor H). HDM-FH has been found to be highly effective in experimental rodent models of kidney disease. HDM-FH should have a clear use in transplantation. The complement system normally protects against invading pathogens and helps to clear cellular waste in our bodies. However, complement can become over active and it drives inflammation. In transplantation, the transplanted organ can be detected as non-self (like a pathogen) and activation of complement can lead to organ rejection. This rejection can be immediate or can take years due to complex processes that are triggered by the complement activation. Thus, preventing complement activation and associated cellular/organ injury during the first minutes of transplantation will significantly prolong the survival of transplanted organ and the well being of the transplant recipient. In Newcastle, we are working on methods to improve the function of kidney through a technique call ex vivo normothermic machine perfusion (EVNP for short), i.e. organs destined for transplant are warmed up with oxygenated blood flow in the lab and allowed to recover from the shock of being transported between hospitals (in cold liquids with no oxygen) prior to organ transplant. EVNP has shown promise in the re-conditioning of organs that might otherwise have been deemed unfit for transplant. Our plan is to try to further improve the outcome of transplanted organs after EVNP by using this system to introduce our anti-complement drug to the kidney, where it can bind and wait until the organ is transplanted into the recipient. Upon transplant, HDM-FH will then act as an organ defence against the recipients immune system. In this study, we will model exposure of human (discarded human kidneys - deemed unfit for transplant by transplant surgeons) and pig kidney (similar size etc to human, readily available from farm production) to the drug and assess how well it remains bound to the organ during EVNP. We will then model, by using whole blood in the EVNP system in the lab, whether we can show complement activation on the organ and that our drug can reverse that. After the successful completion of these experiments, we would use EVNP of pig kidney and transplantation into a small number of pigs (up to 12) to test our drugs in as robust a fashion as possible. These pig transplant experiments (in conjunction with existing data on pig kidney EVNP) would provide important evidence of the ability of our anti-complement drug to protect kidney in a whole animal system. We will be able to assess safety of the drug and any unexpected events with its use. These studies would guide us in the steps to testing these drugs in human transplant studies. Additionally, the success of these drugs in protecting kidneys from complement could lead to the use of the drugs in other situations where complement needs to be controlled, such as the rare kidney disease, C3G.Overall, this research is designed to lead to better organ transplant success, even from organs which are considered borderline for transplant. It will eventually be of significant benefit to the many thousands of people waiting on a renal transplant.

肾移植是肾衰竭患者的金标准治疗方法。然而，器官的供应在数量和质量上都是有限的。这就需要移植捐献者死亡后捐献的肾脏或来自与风险增加相关的非最佳捐献者的肾脏。这些肾脏与长时间没有足够的氧气供应和细胞损伤增加有关，导致移植后立即增加器官损伤。这会缩短肾脏的长期存活时间，导致患者需要再次移植，从而加剧器官短缺危机。我们开发了一种基于称为 H 因子的血液防御蛋白及其相关蛋白的新型抗补体疗法。我们的药物称为 HDM-FH（同二聚最小因子 H）。已发现 HDM-FH 在肾病实验啮齿动物模型中非常有效。 HDM-FH在移植方面应该有明确的用途。补体系统通常可以防止病原体入侵，并有助于清除体内的细胞废物。然而，补体可能变得过度活跃并引发炎症。在移植中，移植的器官可以被检测为非自身器官（如病原体），并且补体的激活可以导致器官排斥。由于补体激活触发的复杂过程，这种排斥可能是立即发生的，也可能需要数年时间。因此，在移植的最初几分钟内防止补体激活和相关的细胞/器官损伤将显着延长移植器官的存活和移植受体的健康。在纽卡斯尔，我们正在研究通过一种称为离体常温机器灌注（简称 EVNP）的技术来改善肾脏功能，即在实验室中用含氧血流对要移植的器官进行预热，并在器官移植前从医院之间运输（在无氧的冷液体中）的冲击中恢复过来。 EVNP 在修复可能被认为不适合移植的器官方面显示出了希望。我们的计划是通过使用该系统将我们的抗补体药物引入肾脏，在那里它可以结合并等待器官移植到受体中，从而进一步改善 EVNP 后移植器官的结果。移植后，HDM-FH 将作为器官防御受体免疫系统。在这项研究中，我们将模拟人类（废弃的人类肾脏 - 移植外科医生认为不适合移植）和猪肾（与人类相似的大小等，可从农场生产中轻松获得）对药物的暴露，并评估 EVNP 期间药物与器官的结合程度。然后，我们将通过在实验室的 EVNP 系统中使用全血来建模，我们是否可以显示器官上的补体激活，以及我们的药物是否可以逆转这种情况。成功完成这些实验后，我们将使用猪肾 EVNP 并移植到少量猪（最多 12 头）中，以尽可能稳健的方式测试我们的药物。这些猪移植实验（结合猪肾 EVNP 的现有数据）将为我们的抗补体药物在整个动物系统中保护肾脏的能力提供重要证据。我们将能够评估药物的安全性及其使用过程中发生的任何意外事件。这些研究将指导我们在人体移植研究中测试这些药物的步骤。此外，这些药物在保护肾脏免受补体影响方面的成功可能会导致在其他需要控制补体的情况下使用这些药物，例如罕见的肾病 C3G。 总的来说，这项研究旨在提高器官移植的成功率，即使是那些被认为是移植边缘的器官。它最终将为成千上万等待肾移植的人带来巨大的好处。

项目成果

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

• DOI: 10.3389/fimmu.2021.752916
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Kamala O;Malik TH;Hallam TM;Cox TE;Yang Y;Vyas F;Luli S;Connelly C;Gibson B;Smith-Jackson K;Denton H;Pappworth IY;Huang L;Kavanagh D;Pickering MC;Marchbank KJ
• 通讯作者: Marchbank KJ

244 The role of the complement system in DCD liver transplantation

244 补体系统在 DCD 肝移植中的作用

• DOI: 10.1016/j.imbio.2023.152694
• 发表时间: 2023
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Mahendran B

Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)-driven Complement-mediated Diseases.

• DOI: 10.1111/imr.13141
• 发表时间: 2023-01
• 期刊: Immunological reviews
• 影响因子: 8.7

38 Evaluation of minimal Factor H therapy administered to kidneys during ex vivo normothermic perfusion as a treatment to improve ischaemia reperfusion injury

38 在离体常温灌注期间对肾脏进行最小 H 因子治疗作为改善缺血再灌注损伤的治疗的评估

• DOI: 10.1016/j.imbio.2023.152492
• 发表时间: 2023
• 期刊: Immunobiology
• 影响因子: 2.8
• 作者: Connelly C

O043 Evaluation of minimal factor H therapy administered to kidneys during ex vivo normothermic perfusion as a treatment to improve ischaemia reperfusion injury

O043 离体常温灌注期间对肾脏进行最小因子 H 治疗作为改善缺血再灌注损伤的治疗的评估

• DOI: 10.1093/bjs/znad101.043
• 发表时间: 2023
• 期刊: British Journal of Surgery
• 影响因子: 9.6
• 作者: Connelly C