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The role of altered monocyte activity in the long-term potential of peritoneal dialysis as a therapy

Final Report Summary - ROAMINPD (The role of altered monocyte activity in the long-term potential of peritoneal dialysis as a therapy)

Worldwide, >250,000 individuals rely on peritoneal dialysis (PD) as a major modality of renal replacement therapy for treating end-stage renal failure. Despite treatment advance in the past three decades, PD-related peritonitis remains one of the major causes for treatment failure as well as patient mortality. Despite the general acceptance that monocyte/macrophages are a frontline component of peritoneal host defense to infection, the immunobiology of this key cell population remains poorly understood.

The aim of our project was to:
1. To complete a contemporary systematic and detailed study of the impact of peritoneal dialysis on the monocyte/macrophage system, including the identification of corresponding subsets between mouse and human.
2. To assess the impact of this altered cell biology on functional responses of PD monocytic cells to infectious challenge, the regulation of immunity and tissue damage.

In this study, we applied contemporary immunological techniques to perform a full phenotypic and functional characterisation of distinct peritoneal monocytic subsets through the course of PD therapy, from one week after PD catheter implantation to 6 months after the dialysis commencement. Firstly, we have performed a detailed immunophenotyping as well as expression profiles of relevant surface markers on peritoneal monocytic cells from PD patients at different stages by advanced multi-colour flow cytometry. Our findings indicated human peritoneal monocyte/macrophages comprise several discrete subpopulations, which cannot be simply classified into a single conventional population, i.e. ‘CD14+ cells’. Individual subsets had differential marker profiles representing various stages of macrophage activation, differentiation and maturation. More importantly, the numbers and the distributions of distinct macrophage subsets were altered by the dialysis process. We have observed, along the course of PD therapy, the decrease in total number of peritoneal macrophages, though their proportion within total peritoneal leukocytes increase considerably. Additionally, our data suggested circulating blood monocytes are recruited into peritoneal cavity, where they became more mature. However, this process has been perturbed by continuous dialysis intervention as peritoneal macrophages resemble blood monocytic phenotype.

Secondly, we have conducted a variety of functional assays to better characterize the distinct peritoneal macrophage subsets we have identified. The functional analysis included ex vivo phagocytosis capacity assay, respiratory burst assay to detect reactive oxygen species generation upon microbial challenges, intracellular cytokine production (e.g. TNF-α, IL-1β, IL-6) in response to exogenous stimuli, and in vitro antigen presentation/T cell stimulation assay. The results, in general, revealed that human peritoneal macrophages from PD patients retain a wide range of functional capabilities. However, differential functional profiles have been noted among the distinct subpopulations, i.e. some with relatively poor phagocytic properties, but with superior antigen presentation ability (more “dendritic cell-like”). This functional diversity suggested individual monocytic subsets may play different roles upon the host-pathogen interaction and in the process of inflammation/resolution within the peritoneal cavity.