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

腹膜树突状细胞在组织特异性免疫中的作用及腹膜透析的临床应用

• 批准号: MR/K02003X/1
• 负责人: Philip Taylor
• 金额: $ 57.57万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK02003X%2F1
• 关键词: Defining; role; peritoneal; dendritic; cells

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.

全球有超过 200,000 人依靠腹膜透析 (PD) 来治疗肾衰竭。在发展中经济体国家，这一数字每年增长 30%。然而，只有三分之一的 PD 患者能够继续治疗 3 年以上。部分原因是终末期肾衰竭患者的死亡率高得令人无法接受，而且复合技术的失败阻碍了 PD 作为临床治疗的长期使用。造成这一问题的主要因素是腹膜感染和炎症驱动的纤维化（组织损伤），导致腹膜衰竭，在少数情况下，会导致严重的包膜性腹膜硬化（肠道被受损的膜包封）。腹膜纤维化的发展与治疗持续时间和细菌性腹膜炎的重复发生率有关。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与一类特定的免疫反应有关，可以保护我们免受感染，但在腹膜腔的情况下似乎对膜有害。疾病进展的实验模型得出了类似的结论，即 IFN-γ 反应会促进纤维化。我们在患者的透析液中发现了新的免疫刺激树突状细胞亚群，并观察到它们的保留量越来越多且不成比例。我们还在实验模型中看到在炎症期间具有类似活性的等效细胞。这些树突状细胞是 IL-12（以及与 IFN-γ 反应相关的免疫信号分子）的有效诱导物，因此是这种对组织有害的 IFN-γ 相关免疫反应的潜在驱动因素。本研究采用复杂的体内建模创新方法，并应用临床样本方法来确定组织特异性树突状细胞在宿主针对腹膜攻击的保护性 Th1 样免疫发展中的作用。我们将检查这些细胞的功能活动、它们被募集并保留在组织中的机制，并探讨操纵它们活动的潜力。我们的提案利用了复杂的体内建模的创新方法，以及临床样本的应用方法，并解决了这一点与 PD 作为一种疗法的长期潜力之间的联系。我们将表征帕金森病患者和实验模型中新发现的细胞。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，从而评估靶向免疫调节疗法改善疾病的潜力。

项目成果

The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal.

• DOI: 10.1126/science.1251414
• 发表时间: 2014-05-09
• 期刊: Science (New York, N.Y.)
• 作者: Rosas M;Davies LC;Giles PJ;Liao CT;Kharfan B;Stone TC;O'Donnell VB;Fraser DJ;Jones SA;Taylor PR
• 通讯作者: Taylor PR

Tissue-resident macrophages.

• DOI: 10.1038/ni.2705
• 发表时间: 2013-10
• 期刊: Nature immunology
• 影响因子: 30.5

Tissue-resident macrophages: then and now.

• DOI: 10.1111/imm.12451
• 发表时间: 2015-04
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Davies LC;Taylor PR
• 通讯作者: Taylor PR

Interleukin-6 signaling drives fibrosis in unresolved inflammation.

• DOI: 10.1016/j.immuni.2013.10.022
• 发表时间: 2014-01-16
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Fielding, Ceri A.;Jones, Gareth W.;McLoughlin, Rachel M.;McLeod, Louise;Hammond, Victoria J.;Uceda, Javier;Williams, Anwen S.;Lambie, Mark;Foster, Thomas L.;Liao, Chia-Te;Rice, Christopher M.;Greenhill, Claire J.;Colmont, Chantal S.;Hams, Emily;Coles, Barbara;Kift-Morgan, Ann;Newton, Zarabeth;Craig, Katherine J.;Williams, John D.;Williams, Geraint T.;Davies, Simon J.;Humphreys, Ian R.;O'Donnell, Valerie B.;Taylor, Philip R.;Jenkins, Brendan J.;Topley, Nicholas;Jones, Simon A.
• 通讯作者: Jones, Simon A.

Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation.

• DOI: 10.1038/ncomms2877
• 发表时间: 2013
• 期刊: Nature communications
• 影响因子: 16.6