Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH)

Brennan, Paul; Macmillan, Maureen S.; Manship, Thomas; Moroni, Francesca; Glover, Alison; Graham, Catriona; Semple, Scott; Morris, David; Fraser, Alasdair R.; Pass, Chloe; McGowan, Neil; Turner, Marc; Lachlan, Neil; Dillon, John; Campbell, John; Fallowfield, Jonathan; Forbes, Stuart J.

doi:10.1136/bmjopen-2021-053190

Cited by 26 publications

(17 citation statements)

References 44 publications

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“…Histologically, we observed the formation of large necroinflammatory foci, which probably reflects that apoptotic hepatocytes were not removed by macrophages, a process that is crucial for the maintenance of liver health and homeostasis [34]. These results support the evaluation of macrophages as a potential cell-based therapy for the control of HDV-induced liver damage, a strategy that is currently being evaluated in clinical trials for the treatment of liver cirrhosis [35].…”

Section: Discussionsupporting

confidence: 64%

Protective Role of RIPK1 Scaffolding against HDV-Induced Hepatocyte cell death and the Significance of Cytokines in Mice

Camps,

Maestro,

Torella

et al. 2023

Preprint

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Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-α treatment. In the present study, we found that TNF-α is mainly produced by macrophages. Downstream of the TNF-α receptor (TNFR), the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serves as a cell fate regulator, playing roles in both cell survival and death pathways. In this study, we explored the function of RIPK1 and other host factors in HDV-induced cell death. We determined that the scaffolding function of RIPK1, and not its kinase activity, offers partial protection against HDV-induced apoptosis. A reduction in RIPK1 expression in hepatocytes through Cas9-mediated gene editing significantly intensifies HDV-induced damage. Contrary to our expectations, the protective effect of RIPK1 was not linked to TNF-α or macrophage activation, as their absence did not alter the extent of damage. Intriguingly, in the absence of RIPK1, macrophages confer a protective role. However, in animals unresponsive to type-I IFNs, RIPK1 downregulation did not exacerbate the damage, suggesting RIPK1's role in shielding hepatocytes from type-I IFN-induced cell death. Interestingly, while the damage extent is similar between IFNAR KO and WT mice in terms of transaminase elevation, their cell death mechanisms differ. In conclusion, our findings reveal that HDV-induced type-I IFN production is central to inducing hepatocyte death, and RIPK1's scaffolding function offers protective benefits. Thus, type-I IFN together with TNFα, contribute to HDV-induced liver damage. These insights may guide the development of novel therapeutic strategies to mitigate HDV-induced liver damage and halt disease progression.

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Section: Discussionsupporting

confidence: 64%

Protective Role of RIPK1 Scaffolding against HDV-Induced Hepatocyte cell death and the Significance of Cytokines in Mice

Camps,

Maestro,

Torella

et al. 2023

Preprint

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“…Alternatively, pre-conditioning treatment with adoptively transferred pro-regenerative macrophage therapy could also be beneficial. This hypothesis is in support of the use of macrophages for the treatment of liver cirrhosis 22 (Phase II trial recently completed; ISRCTN10368050) and alternatively activated, pro-regenerative macrophages for experimental acetaminophen (APAP) liver injury 13 . Future studies can now focus on small experimental deviations but with higher n numbers for statistical power.…”

Section: Discussionmentioning

confidence: 64%

Utilising an in silico model to predict outcomes in senescence-driven acute liver injury

Ashmore-Harris,

Antonopoulou,

Aird

et al. 2023

Preprint

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Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet demand and transplant recipients require lifelong immunosuppression. The identification of alternative treatments, e.g. cell therapies, able to tip resolution of injury from inflammation to regeneration requires an understanding of the host response to the degree of injury. We adopt a combined in vivo-in silico approach and develop a mathematical model of acute liver disease able to predict the host response to injury. We utilise the Mdm2fl/fl mouse model together with a single Cre induction through intravenous injection of the hepatotropic Adeno-associated Virus Serotype 8 Cre (AAV8.Cre) to model acute liver injury. We derive a complementary ordinary differential equation model to capture the dynamics of the key cell players in the injury response together with the extracellular matrix. We show that the mathematical model is able to predict the host response to moderate injury via qualitative comparison of the model predictions with the experimental data. We then use the model to predict the host response to mild and severe injury, and test these predictions in vivo, obtaining good qualitative agreement.

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“…Similarly exogenous macrophage treatments were shown to promote injury resolution in a several murine models of inflammatory and degenerative diseases including pulmonary fibrosis and osteochondral defect [64,65]. This successful demonstration of macrophage therapy in pre-clinical models led to the use of autologous macrophages in therapeutic interventions in clinical studies against chronic liver injury and neurodegenerative diseases [66,67]. It is thought that these repair functions are performed by the anti-inflammatory or resolving M2-polarized macrophages and several studies identified iPSCs-derived macrophages to be able to be polarized into an M2-phenotype similar to MDMs [30].…”

Section: Ipscs-derived Macrophages In Cell and Regenerative Therapymentioning

confidence: 97%

Pluripotent Stem Cell Derived Macrophages: Current Applications and Future Perspectives

Jose¹,

Forrester²

2022

Macrophages - Celebrating 140 Years of Discovery

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The ability to derive macrophages from human-induced pluripotent stem cells (iPSCs) provides an unlimited source of genotype-specific cells with the potential to play a role in advancing our understanding of macrophage biology in both homeostasis and disease. While sharing many of the functional characteristics of monocyte-derived macrophages, iPSC-derived macrophages have also been shown to have phenotypical and functional features associated with tissue resident macrophages. These features present new opportunities to develop models of human disease and to understand the role of developmental or tissue context in innate immune cell function. iPSCs-derived macrophages have also been identified as a highly attractive source for cell and gene therapy in the treatment of diverse degenerative diseases based on their anti-inflammatory activity, their ability to clear scarred cells by phagocytosis, and providing extracellular matrices. We review and present a concise discussion on macrophage differentiation from stem cells highlighting their advantages over classical monocyte-derived macrophages in modelling organ specific macrophages. We summarize the various disease models utilizing iPSCs-derived macrophages including hereditary syndromes and host-pathogen interactions in tissue repair and the strategies used to mimic pathological phenotypes. Finally, we describe the pre-clinical studies that have addressed the application of iPSCs-derived macrophages as a therapeutic intervention.

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Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH)

Cited by 26 publications

References 44 publications

Protective Role of RIPK1 Scaffolding against HDV-Induced Hepatocyte cell death and the Significance of Cytokines in Mice

Protective Role of RIPK1 Scaffolding against HDV-Induced Hepatocyte cell death and the Significance of Cytokines in Mice

Utilising an in silico model to predict outcomes in senescence-driven acute liver injury

Pluripotent Stem Cell Derived Macrophages: Current Applications and Future Perspectives

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