Can differences in Th1 IFNg-to-IL-10 cytokine switching mediated by CD46 predict functional outcome after renal transplantation?

CD46 介导的 Th1 IFNg 至 IL-10 细胞因子转换的差异能否预测肾移植后的功能结果？

• 批准号: MR/N020340/1
• 负责人: Harriet Douthwaite
• 金额: $ 28.68万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN020340%2F1
• 关键词: differences; Th1; IFNg; IL; 10

Kidney transplantation is the preferred treatment for kidney failure, offering a better quality of life & economic benefits compared to dialysis. However, most kidney transplants do not survive as long as recipients (approximately 10-15 years) so renal graft failure accounts for 30% of those returning to dialysis and increases the demand for organs that are already in short supply. The commonest cause of graft failure is an immune response known as chronic rejection (CR). Surprisingly little is known about the mechanisms that cause CR. Patients with detectable antibodies released by B cells are known to be at higher risk of CR but this alone has been an insufficient explanation. Research has shown that there are a number of important immunologic factors involved including T cells, B cells, cell-signalling proteins known as cytokines and the complement system (part of the innate and adaptive immune system). There is growing evidence that it is the delicate interactions between these components that underpin CR. T cells respond to specific pathogens within cells or cells recognised to be 'non self'. Different T cells have different functions but work together and with B cells. T helper 1 (Th1) cells are a subset of CD4+ T cells and play a major role in organ rejection or alloimmunity. Th1 cells release an inflammatory cytokine known as Interferon gamma (IFNg). However, its release is controlled by another cytokine IL-10, otherwise uncontrolled IFNg production results in severe tissue damage & death. Recent research (by co-supervisor CK) shows that the complement system also plays a critical role in the release and regulation of IFNg. This is known as the concept of 'IFNg to IL-10 switching '. Abnormalities of this switching process (either by failure to stop IFNg release or failure to produce IL-10) leads to hyperactive Th1 responses, seen in autoimmune diseases such as Rheumatoid arthritis & multiple sclerosis. There are obvious attractions to the development of therapeutic control of Th1 pathway i.e. locking cells into a desired functional state. The primary supervisor (AD) has conducted research into the role of the B cells in CR. B cells present 'foreign' proteins known as antigens from the donated kidney to CD4+ T cells. AD has shown that the rate of functional decline is significantly faster in patients where the B cells present antigen. He has developed an assay to detect CD4+T cells responses and release of IFNg. Antigen presentation by B cells has been shown to stimulate and to suppress IFNg in vitro & immune-mediated injury to the graft. In patients where B cells activity suppresses IFNg release there is also evidence of IL-10 production. Mechanisms that regulate IFNg therefore appear to be critical determinants of transplant success. The aim of the proposed research is to investigate 'IFNg to IL-10 switching' in alloimmunity & test the hypothesis that in patients with CR, failure of the 'IL-10 switch' is associated with functional decline, graft loss & return to dialysis. Detection, management & prevention of CR presents major challenges to transplant medicine & the understanding how the cells interact is crucial for novel strategies to promote long-term graft survival.

肾移植是肾衰竭的首选治疗方法，与透析相比，它提供了更好的生活质量和经济效益。然而，大多数肾移植患者的存活时间不长（约10-15年），因此肾移植失败占那些返回透析的患者的30%，并增加了对已经短缺的器官的需求。 移植失败的最常见原因是被称为慢性排斥反应（CR）的免疫反应。令人惊讶的是，人们对导致CR的机制知之甚少。已知具有可检测到的由B细胞释放的抗体的患者CR的风险较高，但仅这一点并不能充分解释。研究表明，有许多重要的免疫因素参与，包括T细胞，B细胞，细胞信号蛋白称为细胞因子和补体系统（先天性和适应性免疫系统的一部分）。越来越多的证据表明，正是这些组件之间的微妙相互作用支撑了CR。 T细胞对细胞内的特定病原体或被识别为“非自身”的细胞作出反应。不同的T细胞有不同的功能，但一起工作，并与B细胞。辅助性T细胞1（Th 1）是CD 4 + T细胞的一个亚群，在器官排斥或同种异体免疫中起主要作用。Th 1细胞释放称为干扰素γ（IFNg）的炎性细胞因子。然而，其释放由另一种细胞因子IL-10控制，否则不受控制的IFNg产生导致严重的组织损伤和死亡。最近的研究（由共同主管CK）表明，补体系统在IFNg的释放和调节中也起着关键作用。这被称为“IFNg至IL-10转换”的概念。这种转换过程的中断（无论是由于未能阻止IFNg释放还是未能产生IL-10）都会导致Th 1反应过度活跃，见于自身免疫性疾病，如风湿性关节炎和多发性硬化症。Th 1通路的治疗控制的发展有明显的吸引力，即将细胞锁定到期望的功能状态。 主要主管（AD）已对CR中B细胞的作用进行了研究。B细胞将来自捐赠肾脏的“外来”蛋白质（称为抗原）呈递给CD 4 + T细胞。AD已经表明，在B细胞呈递抗原的患者中，功能下降的速率显著更快。他开发了一种检测CD 4 +T细胞反应和IFNg释放的方法。已显示B细胞的抗原呈递在体外刺激和抑制IFNg &对移植物的免疫介导的损伤。在B细胞活性抑制IFNg释放的患者中，也有IL-10产生的证据。因此，调节IFNg的机制似乎是移植成功的关键决定因素。 拟议研究的目的是研究同种异体免疫中的“IFNg至IL-10转换”，并检验以下假设：在CR患者中，“IL-10转换”失败与功能下降、移植物丢失和恢复透析相关。CR的检测、管理和预防对移植医学提出了重大挑战，了解细胞如何相互作用对于促进移植物长期存活的新策略至关重要。