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

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，大多数肾移植不能和受者一样存活很长时间（大约10-15年），因此肾移植衰竭占再次透析患者的30%，这增加了对已经供应不足的器官的需求。移植失败最常见的原因是一种被称为慢性排斥反应（CR）的免疫反应。令人惊讶的是，人们对引起CR的机制知之甚少。已知B细胞释放出可检测抗体的患者发生CR的风险较高，但仅凭这一点还不足以解释CR。研究表明，有许多重要的免疫因子参与其中，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，正是这些成分之间的微妙相互作用支撑着CR。T细胞对细胞内的特定病原体或被识别为“非自我”的细胞做出反应。不同的T细胞有不同的功能，但与B细胞一起工作。T辅助1 （Th1）细胞是CD4+ T细胞的一个亚群，在器官排斥或同种免疫中起主要作用。Th1细胞释放一种称为干扰素γ (IFNg)的炎症细胞因子。然而，它的释放受另一种细胞因子IL-10的控制，否则不受控制的IFNg产生会导致严重的组织损伤和死亡。最近的研究表明，补体系统在IFNg的释放和调节中也起着关键作用。这就是所谓的“IFNg到IL-10转换”的概念。这种转换过程的异常（由于不能阻止IFNg释放或不能产生IL-10）导致过度活跃的Th1反应，见于类风湿性关节炎和多发性硬化症等自身免疫性疾病。对Th1通路的治疗性控制的发展有明显的吸引力，即将细胞锁定到所需的功能状态。主监管者（AD）已经对B细胞在CR中的作用进行了研究，B细胞将来自捐赠肾脏的抗原“外来”蛋白质呈现给CD4+ T细胞。阿尔茨海默病表明，在B细胞呈抗原的患者中，功能下降的速度明显更快。他开发了一种检测CD4+T细胞反应和IFNg释放的方法。B细胞的抗原呈递已被证明在体外刺激和抑制IFNg和免疫介导的移植物损伤。在B细胞活性抑制IFNg释放的患者中，也有证据表明IL-10的产生。因此，调节IFNg的机制似乎是移植成功的关键决定因素。拟议研究的目的是调查同种免疫中的“IFNg到IL-10转换”，并验证CR患者中“IL-10转换”失败与功能下降、移植物丢失和重返透析相关的假设。CR的检测、管理和预防是移植医学面临的主要挑战，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。

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.