Robertson, F; (2018) The effect of remote ischaemic preconditioning on CD4 T cells following hepatic ischaemia reperfusion injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ischaemia Reperfusion (IR) injury is a major cause of morbidity and mortality following orthotopic liver transplantation. Remote Ischaemic Preconditioning (RIPC) reduces IR injury in small animal models. The mechanism remains unclear. The aim of this thesis was to explore the mechanism of RIPC and its clinical relevance to liver transplant recipients. Following a literature review a study was performed on optimal end points for clinical studies modulating IR injury in liver transplantation. Day 3 AST level was strongly associated with early post operative morbidity and mortality. A pilot randomised controlled trial of limb RIPC (3 cycles 5 minutes) in 40 liver transplant recipients was performed. Recruitment was successful and the intervention found to be safe and well tolerated. There was no significant difference in day 3 AST. CD4+T cell IFNγ and TNFα production was found to be significantly upregulated in patients post-reperfusion but not affected by RIPC. IFNγ and IL-2 were produced by a CD3-ve HLADR+ve cell population. Monocyte chemoattractant protein-1 (MCP-1) levels were significantly elevated following reperfusion and correlated with clinical outcomes. The T cell response to RIPC was further investigated in a murine model of RIPC and warm liver IR injury. The model demonstrated a reduction in warm liver IR injury following RIPC. Intrahepatic CD4+ T cell TNFα production was significantly increased following reperfusion and reduced by RIPC. Monocytes were recruited to the post ischaemic liver as demonstrated in the human clinical trial. MCP-1 levels and monocyte recruitment were significantly reduced following RIPC in the mouse. In conclusion clinical benefit of RIPC in OLT recipients was not achieved in this pilot study. The RIPC stimulus may be sub-optimal. CD4+T cells and monocytes were shown to have a key role in both the human and animal studies and their manipulation may provide new opportunities for modulating liver IR injury.

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