Engelmann, Cornelius; (2022) Synergisms of stem cell mobilisation and toll-like receptor 4 inhibition to treat the acute-on-chronic liver failure. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: The acute-on-chronic liver failure (ACLF) is a complex disease with high mortality without effective therapeutic opportunities. A greater understanding of disease mechanisms is necessary to identify novel targets for disease modifying therapies. Systemic inflammation is central and toll-like receptor 4 (TLR4) may be an important pathway involved in activating immune cells. Granulocyte-colony stimulating factor (G-CSF) mobilises immunomodulatory stem- and immune cells and pivotal clinical studies provided promising results in liver disease. Aims: I aimed to understand the role of TLR4 in mediating inflammation and organ injury in ACLF. I also explored how G-CSF exerts its immunomodulatory capacities in ACLF and whether combing G-CSF with TLR4 signalling inhibition by TAK-242 might act synergistically. Methods: The first experimental part comprised human samples, and septic ACLF rodent models in which I evaluated the role of TLR4 in mediating inflammation and organ injury. The second clinical part was based on a multicentre interventional trial evaluating the impact of G-CSF on the outcome of humans with ACLF. In the third experimental part G-CSF and TAK-242 were used as therapy in a septic and in a sterile ACLF mouse model to evaluate synergisms of both therapies. Results: The first part showed that TLR4 signalling prompted cytokine release and organ injury causing deaths in ACLF. TLR4 signalling inhibition by TAK-242 prevented tissue injury and fatalities. The clinical trial revealed that G-CSF was ineffective in ACLF. In the septic mouse model of ACLF GCSF alone exaggerated the inflammatory response. The combinatory therapy G-CSF plus TAK-242 acted synergistically by reducing organ injury and promoting tissue repair. Conclusion: This study highlighted the complexity of ACLF and introduced TLR4 mediated inflammation as a central pathomechanistic element. It also emphasized that combinatory therapies may be necessary to address the whole spectrum of pathomechanisms involved in ACLF.

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