Unconventional T-cell driven inflammatory responses during acute peritonitis : implications for diagnosis and therapy of peritoneal dialysis patients

• Main Author: Liuzzi, Anna Rita
• Published: Cardiff University 2016
• Subjects: 617.4; R Medicine (General)
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690933

Scientific background. Infection remains a major cause of morbidity and technique failure in PD patients. The mechanisms that underpin the clinical severity of peritonitis episodes and their link to outcomes remain poorly defined. γδ T cells together with MAIT cells play a crucial role in orchestrating acute immune responses by the recognition of metabolites (HMB-PP and vitamin B2 derivatives) present in many pathogenic bacteria. My work aimed to understand the molecular and cellular mechanisms underlying the local recognition of bacterial pathogens by peritoneal unconventional T cells, which could be exploited for targeted therapies and novel point of care diagnostic test. Approach. The local and systemic frequency of unconventional T was analysed before and during acute microbial infections, in a well-defined cohort of individuals with end-stage kidney disease receiving peritoneal dialysis (PD). In addition, the responsiveness of peritoneal unconventional T cells to HMB-PP and/or vitamin B2 producing bacteria was assessed ex vivo. Results. This study demonstrated that: (i) peritoneal Vγ9/Vδ2 T cells and MAIT cells are elevated in patients with infections caused by HMB-PP and/or vitamin B2 positive bacteria (e.g. E. coli) but not in infections caused by HMB-PP and vitamin B2 negative species (e.g. Streptococcus ); (ii) peritoneal Vγ9/Vδ2 T cells and MAIT cells are dominant producers of the pro-inflammatory cytokines TNF-α and IFN-γ in response to HMB-PP and/or vitamin B2 positive bacteria; and (iii) in turn, TNF-α and IFN-γ are potent stimulators of peritoneal mesothelial cells and fibroblasts. Outcome analyses showed that infections caused by bacteria that are able to activate Vγ9/Vδ2 T-cells and/or MAIT cells were associated with higher risks of technique failure such as mortality and catheter removal. Conclusions. My studies provide a molecular basis for the existence of pathogen-specific immune fingerprints that have diagnostic and prognostic value, identify key pathways by which unconventional T-cells can amplify early inflammatory responses, and highlight potential therapeutic targets that may be exploited to improve outcomes.