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

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.

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 partly due to unacceptably high mortality rate for end-stage renal failure patients, and compounding technique failures which prevent the long-term use of PD. Development of peritoneal fibrosis is linked to treatment duration, and repeated incidence of bacterial peritonitis.

In PD patients, we have found that loss of membrane function is associated with the presence of IFN-gamma (correlated with IL-6) in dialysate while in an experimental model of multiple inflammatory episode-induced fibrosis, tissue pathology was dependent on IL-6, IFN-gamma and STAT1.

We have identified a relative accumulation of novel dendritic cells (DC) in PD patient dialysate and have characterised cells with similar phenotype and responses to infection in experimental models. These novel DC are the major local producers of IL-12, represent the front line in response to microbial infection and may be key mediators of the tissue damaging IFN-gamma responses. This proposal will use powerful approaches (e.g. global transcriptional analysis and innovative in vivo modelling with adoptive transfers and in vivo lentiviral modification) to define: i) the role of peritoneal DC in inflammation-induced specific immunity; ii) the mechanisms that underpin the homeostatic and inflammatory trafficking/retention of DC in the peritoneum; iii) the activity of DC during the resolution of inflammation (e.g. their role in clearance of apoptotic cells); and iv) the prognostic value of monitoring peritoneal DC in dialysis patients. This will define novel aspects of clinically relevant tissue specific immunity, the initiation of the chronic disease process and it will also assess the potential of targeted immune-modulation therapies to ameliorate disease.

The main beneficiary with immediate impact would be academia, including academia outside the applicants immediate professional circle. This is because the research will provide basic insights into the generation of tissue-specific immunity and the development of chronic disease. The principles of the project are relevant to other physiological contexts where protection of a 'port of entry' by local dendritic cells dictates the outcome during infection and the development of an immune response. This broadens the scope of the impact to other disciplines, for example, study of other mucosal infectious and/or inflammatory disorders.

A secondary beneficiary with medium term impact would be the Industrial and pharmaceutical sector. Several of the applicants have collaborative or other associations with industry and are well positioned to exploit any novel intellectual property. We would anticipate that the output from this research would lead fairly rapidly to additional industrial collaborations based on our past experience and existing collaborations. Intellectual property would be appropriately protected for exploitation and several of the applicants have experience in this area (see 'Pathways to Impact' for more information)

In the longer term this work should directly benefit patients with infectious or inflammatory diseases as tissue dendritic cell immune surveillance and will be central to many disease outcomes. The application of these studies directly to patient samples and the use of a well-characterised back translated mouse model, which implicates similar mechanistic processes to those seen in human disease will ensure that the work is relevant to human disease. Characterisation of the function of specific tissue immune cells proposed in this application will hence also potentially identify ways in which these cells can be manipulated to to reduce the impact of inflammatory and infectious diseases.

The School of Medicine at Cardiff is very actively engaged in public engagement (see 'Pathways to Impact' and the 'communications plan' for more information). We would hope that the continued involvement of the investigators in these well-recognised and respected public engagement activities would continue to inspire young people towards a career in science and show the research in Cardiff, and the UK as a whole, as internationally leading.