Defining the role of peritoneal dendritic cells in tissue specific immunity and the clinical application of peritoneal dialysis

在世界范围内，> 200，000个体依赖腹膜透析（PD）来治疗肾衰竭。在发展中国家，这一数字每年增长30%。然而，只有三分之一的PD患者设法继续治疗超过3年。这部分是由于终末期肾衰竭患者的死亡率高得不可接受，以及复合技术失败，这阻碍了PD作为临床治疗的长期使用。该问题的主要促成因素是腹膜感染和炎症驱动的纤维化（组织损伤），其导致腹膜衰竭，并且在少数情况下，导致严重的包裹性腹膜硬化（肠被包裹在受损的膜中）。腹膜纤维化的发生与治疗持续时间和细菌性腹膜炎的反复发生有关。我们最近的数据表明，PD患者组织损伤的临床测量与透析液中可检测到的IFN-γ相关。IFN-γ与一类特殊的免疫反应有关，它保护我们免受感染，但在腹膜腔的情况下，它似乎对膜有害。疾病进展的实验建模产生了类似的结论，即IFN-γ应答促进纤维化。我们已经在患者的透析液中鉴定了免疫刺激树突状细胞的新亚群，并观察到它们变得越来越多且不成比例地保留。我们还在实验模型中看到了在炎症过程中具有类似活性的等效细胞。这些树突细胞是IL-12（和与IFN-γ应答相关的免疫信号传导分子）的有效诱导物，因此是对组织有害的这种IFN-γ相关免疫应答的潜在驱动物。本研究采用创新的方法，在复杂的体内建模，并与临床样本的应用方法，以确定组织特异性树突状细胞在宿主保护性Th 1样免疫腹膜挑战的发展中的作用。我们将研究这些细胞的功能活性，它们被招募并保留在组织中的机制，并解决操纵其活性的潜力。我们的建议利用创新的方法在复杂的体内建模，并与临床样本的应用方法，并解决这与PD作为一种治疗的长期潜力之间的联系。我们将在PD患者和实验模型中检测新发现的细胞。总之，我们将定义临床相关组织特异性免疫的新方面，阐明与复发性炎症发作和腹膜纤维化相关的临床问题，并因此评估靶向免疫调节疗法改善疾病的潜力。

Worldwide, >200,000 individuals rely on peritoneal dialysis (PD) for treatment of renal failure. In countries with developing economies this figure grows by 30% each year. However, only a third of PD patients manage to continue therapy beyond 3 years. This is in part due to an unacceptably high mortality rate for end-stage renal failure patients, and compounding technique failures which prevent the long-term use of PD as a clinical therapy. The main contributing factors to this problem are peritoneal infection, and inflammation-driven fibrosis (tissue damage) that leads to peritoneal membrane failure and, in a minority of cases, a severe encapsulating peritoneal sclerosis (encapsulation of the intestine in damaged membrane). Development of peritoneal fibrosis is linked to treatment duration, and repeated incidence of bacterial peritonitis. Our recent data indicates that clinical measures of tissue damage in PD patients are associated with detectable IFN-gamma in dialysis fluid. IFN-gamma is associated with a specific class of immune response which protects us from infection, but which in the case of the peritoneal cavity appears detrimental to the membrane. Experimental modelling of disease progression produces similar conclusions that an IFN-gamma response promotes fibrosis. We have identified novel subsets of immune stimulating dendritic cells in the dialysis fluid of patients and observed that they become increasingly and disproportionately retained. We also see equivalent cell in experimental models with similar activities during inflammation. These dendritic cells are potent induces of IL-12 (and immune signalling molecule associated with IFN-gamma responses) and hence potential drivers of this IFN-gamma associated immune response that is detrimental to the tissue. This study uses innovative approaches in sophisticated in vivo modelling, and applied approaches with clinical samples to determine the role of tissue specific dendritic cells in the development of host protective Th1-like immunity to peritoneal challenge. We will examine the functional activity of these cells, the mechanism by which they are recruited to and retained in the tissue and address the potential of manipulating their activity. Our proposal utilises innovative approaches in sophisticated in vivo modelling, and applied approaches with clinical samples, and address links between this and the long term potential of PD as a therapy. We will characterise newly identified cells in both PD patients and experimental models. In summary, we will define novel aspects of clinically relevant tissue specific immunity, shed light on the clinical issues associated with recurrent inflammatory episodes and peritoneal fibrosis and will hence assess the potential of targeted immune-modulation therapies to ameliorate disease.