Chronic liver disease has a significant impact on the immune system, both locally in the organ and systemically. The implications of immune dysfunction in liver disease can have broad implications, both during disease and after the removal of the liver insult. Our research is rooted in our foundational studies in chronic HCV infection, wherein we observed hyperfunction of immune cells, namely CD8+ T-cells, and altered macrophage function, in the context of advanced liver fibrosis/cirrhosis. This was sustained long after therapeutic cure of the infection. This may bear long-term consequences for HCV reinfection, susceptibility to liver cancer, need to liver transplant, responsiveness to vaccination and overall health status. Moreover, we are seeing that this phenomenon extends to other chronic liver diseases, such as inflammatory fatty liver disease, which is increasing in its clinical prevalence globally at an alarming rate. We are exploring the intersection of immunological dysfunction alongside metabolic upset, which is a critical component of chronic liver disease. We aim to identify novel targets for immunotherapies to develop for those who are affected by advanced liver damage.
Strong partnerships with clinician-scientists inform the posing of our hypotheses, with a focus on translational research. We have established, productive and successful collaborations with clinicians in infectious diseases, hepatology and metabolic disease.
Our research activities are primarily conducted in human cell systems, and we have expanded into the use of animal models of liver disease to deepen our mechanistic and discovery research activities. We implement classical immunology approaches in primary cell culture and immunoassays alongside the latest innovations in cell and molecular analyses (multi-colour flow cytometry, gene expression analyses, biomarker discovery via multiplex protein quantification and more).
Crawley Lab Specific Research Interests
•Identify the underlying mechanisms of CD8+ T-cell dysfunction in chronic liver disease with advanced fibrosis/cirrhosis across disease etiologies (e.g. HCV, HBV, non-alcoholic fatty liver disease. •To examine the underlying mechanisms mediating the altered function of macrophage subsets in chronic liver disease that contribute to tissue homeostasis and mediate liver fibrosis and inflammation. Identification of potential therapeutic targets to mitigate cellular dysfunction and tissue damage are integral to this work.
•Evaluate the interactions between cells of innate and adaptive immunity in the context of the liver, in health and chronic liver disease. Specifically, we aim to evaluate interactions between macrophage subsets, liver-resident macrophages (Kupffer cells) and CD8+ T-cells that influence the function of the latter cells.
•Examine concurrent effects of therapeutics in treating chronic liver disease in the context of changes on the immune system and host metabolism.
•The Crawley Lab Biobank for the Study of Chronic Liver Disease: A shared resource of clinical samples, supported in part by the Canadian Hepatitis C Network www.canhepc.ca/en