Liver Immunology Unit

HeadsProf Golo Ahlenstiel (opens in a new window), Dr Scott Read (opens in a new window)
PhD Student – Dr Ratna Wijaya

The Liver Immunology Research Unit aims to better understand the influence of lifestyle, chronic disease and infection on the hepatic immune system. From clearance of viral infection as is the case with Hepatitis C virus, to the development of severe inflammation and fibrosis due to fatty liver disease, the hepatic immune system possesses both beneficial and damaging roles. Our research focus lies within the innate arm of the immune system, with a specific emphasis on how natural killer (NK) cells and liver macrophages (Kupffer cells) mediate these effects. Our unit is currently located at both the Blacktown Clinical School and Research Centre, Blacktown Hospital, as well as the Westmead Institute for Medical Research, Westmead Hospital. To accomplish our basic research goals, we utilise a number of advanced laboratory techniques including flow cytometry, fluorescence microscopy, genomics and transcriptomics (RNA sequencing), as well as cell culture approaches that include primary cell isolation and organoid culture. We collaborate extensively with external research groups and hospital staff to obtain tissue and blood specimens used for analytical measurements and primary cultures.

Contact: Dr Scott Read

Ongoing projects and student opportunities:

Development of organoid culture systems

Organoids are three dimensional structures grown in vitro from primary tissue that retain the characteristics of their primary source, including self-renewal, organisation, and differentiation. As such, they are an optimal model to study the influence of genetic and environmental factors on disease progression and treatment. Using in vitro co-culture systems, this project will examine the factors that contribute to “leaky gut” in NASH, and how translocating microbes influence liver inflammation. In addition to enteric bacterial, fungal and human viruses, this project contains a unique focus on bacteriophages, and their contribution to chronic immune stimulation in both the gut and liver. This study utilises cutting edge primary cell culture, flow cytometry and molecular biology techniques to discover unknown connections between gutand liver immunity, and will enable a better understanding of inter-organ interactions that contribute to NASH pathogenesis.

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The role of interferon lambda in liver inflammation and fibrosis

Interferon lambda (IFN-λ) is a central antiviral cytokine in the liver that is elevated in NASH, and that contributes to the progression of liver inflammation and fibrosis. The mechanism of IFN-λ induction, and cells involved however, remain unknown. We hypothesise that microbial ligands originating from the gut, enter the liver in the portal blood and stimulate IFN-λ expression. This project aims to determine the contribution and identity of intestinal biota that stimulate IFN-λ, the responsive cells, and the mechanisms by which IFN-λ drives liver inflammation. We will utilise cutting edge genomics, primary cell culture, flow cytometry and molecular biology techniques to shed some light on the role of IFN-λ in NASH. This study will pave the way for future treatments aimed at halting the progression of inflammation in NASH.

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Immune dysregulation in obesity

Obesity is associated with alterations in metabolism, immune function, inflammation and microbiome, however the inter-relationship between these factors remains ill-defined. Blacktown Public Hospital has recently implemented a large healthy weight and bariatric surgical program, which provides the ideal environment to address the poorly understood, but essential aspect of obesity. Samples obtained pre- and post-bariatric surgery will be used to understand how obesity and metabolic syndrome cause immune dysregulation promoting subsequent development of obesity related complications in liver, gut and cardiovascular system. This project will examine the effects of bariatric surgery and subsequent weight loss on systemic, as well as liver and intestinal immune activity and dysregulation. In particular, how rapid weight loss alleviates chronic inflammation and immune exhaustion associated with obesity. Changes in microbiome and intestinal permeability will also be examined with respect to liver inflammation and immunopathology. This project will possess a strong clinical and translational focus, relating immune parameters to clinical outcomes. In vitro analysis of immune cell phenotypes will be performed by flow cytometry, RNAseq and primary liver and intestinal cell culture will be used to elucidate pathological mechanisms.

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The role of zinc in the acute phase response

Zinc is an essential trace element and a key component of numerous transcription factors and enzymes that represent approximately 10% of the human proteome. Importantly, zinc deficiency results in a compromised immune system, as evidenced by thymic atrophy, lymphopenia and defective lymphocyte responses in animal and human studies. The project will examine the role of zinc in the acute phase immune response to viral and bacterial antigens in the liver.

Chronic liver disease is associated with increased gastrointestinal permeability, which subjects the liver to an influx of gut microbes that stimulate the hepatic immune response. Serum amyloid A proteins (SAAs) are swiftly and potently secreted from the liver following encounter with pathogenic and inflammatory stimuli. They facilitate the recruitment of immune cells to inflammatory sites and aid in the degradation of the extracellular matrix. Importantly, SAAs are significantly up-regulated in response to zinc deprivation, suggesting that they may potentiate the inflammatory response to pathogenic stimuli. This project will cutting edge primary cell culture, flow cytometry and molecular biology techniques to understand the molecular mechanisms underlying the induction of SAA proteins, and the subsequent inflammatory effects on immune cells in response to zinc deprivation.

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Immune related memory in liver disease

Immunological memory defines the ability of the immune system to (1) rapidly and specifically recognize an antigen that the body has been previously exposed to and (2) initiate a highly specific immune response. Traditionally, immune related memory is attributed to the adaptive immune response, i.e. T cells and B cells through cytokine release, direct cellular toxicity via antibodies. Natural killer (NK) cells are usually considered part of the innate immune system and considered not to be antigen-specific. However, recent publications suggest that NK cells can, under certain conditions, express memory-like features.

Using state-of-the-art techniques including flow cytometery and CyTOF in in vitro (organoid) and in vivo models (human and mouse), this projects will examine the role of memory-like NK cells in acute and chronic infection as well as autoimmune context with a focus on liver disease to assess their role in pathogenesis, disease progression in liver disease as well as their therapeutic potential in this context.

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Achieving Sustainable Outcomes in Obesity

Obesity is a multifactorial condition associated with a high risk for hypertension, dyslipidaemia, Non-Alcoholic Fatty Liver Disease (NAFLD), diabetes mellitus, cardiovascular complications, stroke, obstructive sleep apnea, osteoarthritis, and even cancers. Despite a growing understanding of disease aetiology and advances in pharmacological therapy, obesity rates have quadrupled between 1986-2000. National statistics from Australian sources predict that normal-weight adults will constitute less than a third of the population by 2025, and that the prevalence of obesity will have increased by 65%.

To cure obesity, long-term weight loss needs to be achieved. While lifestyle interventions can be successful, long-term efficacy results are disappointing. Hence, bariatric Surgery is now considered the most effective modality for sustainable weight loss and for curing co-morbidities. NSW Health has recently invested into the largest publicly funded obesity program in Australia based at Blacktown Hospital that A) provides a multidisciplinary approach to obesity and B) funding for 100 bariatric surgeries per year. Multi-centre ethics covering three large tertiary hospitals and two research centres is approved allowing for longitudinal data collection, biobanking and data linkage.

This provides an opportunity examine the role of nutrition, lifestyle, mental health or metabolic interventions to achieve long-term sustainable outcome in obese patient in the context of a multi- and interdisciplinary setting.

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Drivers of Advanced Liver Disease

Chronic inflammation and altered protein metabolism caused by infection, alcohol, fat or autoimmune disease not only drive progression to end-stage scarring, a state called liver cirrhosis, but also subsequent chronic liver failure and hepatic decompensation with high liver-related mortality. Various markers have been associated with hepatic decompensation, but it remains ill understood what actually initiates the event and how such markers relate to short and long-term survival.

This project aims what to clarify how chronic inflammation and altered protein metabolism contribute to disease progression and activity and clinical severity in advanced liver disease using human samples and mouse models. We will utilise cutting edge genomics, primary cell culture, flow cytometry and/or CyTOF as well as molecular biology techniques. This study will identify new biomarkers predicting clinical outcomes and new targets for therapeutic intervention.

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Current collaborators:

Jacob George (University of Sydney, Westmead Institute for Medical Research), Andrew Harman (Westmead Institute for Medical Research), Dr Grahame Ctercteko & Dr Martijn Gosselink (Colorectal Surgery, Westmead Hospital), Vincent Lam (Upper Gastrointestinal Surgery, Westmead Hospital), Meredith O’Keeffe (Monash University), Carola Venturini & John Iredell (Westmead Institute for Medical Research), Nick King & Helen McGuire (Charles Perkins Centre), John Sebastian Eden (University of Sydney), Patrick Bertolino (Centenary Institute), David Booth (Westmead Institute for Medical Research), Jonel Trebicka (University of Bonn), Andrew Lloyd (University of New South Wales)