Wajahat Mehal, MD, DPhil

Sterile Inflammation: Inflammation occurs in response to tissue injury even in the absence of signals from pathogens. There are numerous examples of this, from soft tissue swelling after trauma to the inflammatory infiltrate after a myocardial infarction. In the liver a number of clinically important conditions have a significant sterile inflammatory component. These include drug induced liver injury, alcoholic, and non-alcoholic liver disease. We have recently identified a two signals pathway consisting of activation of TLR9 by DNA from apoptotic self cells, and also activation of the inflammasome pathway. In addition we have found that the cheap and safe anti-inflammatory drug aspirin can inhibit the TLR9 mediated pathway. We are expanding these findings to test their general applicability to a wide range of liver diseases and also to further identify the role of up-stream activating steps including nuclear DNA, and metabolites of the uric acid pathway.

Liver Fibrosis: The hepatic stellate cell (HSC) is recognized as central to the development of liver fibrosis. We explored the paradigm that signals from dying cells result in HSC activation, and demonstrated that adenosine, which accumulates in conditions of tissue injury and inflammation, results in HSC activation. Interestingly in addition to up-regulating pro-fibrotic genes, adenosine also inhibits cytosolic calcium fluxes resulting in loss of HSC chemotaxis and contractility. We are currently examining other functional consequences of adenosine on HSC.

Liver Immunology: Antigens presented in the liver generate a suboptimal immune response often resulting in their chronic persistence (immune tolerance). This occurs clinically with tolerance to food antigens, to allo-antigens after transplantation, and to viral antigens during chronic infection with hepatitis viruses B and C. Despite these long-standing observations, it was recently realized that the healthy liver contains a large number of T cells (between 4-8 x 106 per gram of tissue). In this population conventional CD8+ T cells, and NK-T cells are over-represented, have an activated phenotype, and are undergoing cell cycle. We are interested in defining the interactions that occur between the healthy liver and the immune system during immune homeostasis, acute viral infections, and presentation of allo-antigens. We have shown that the healthy liver retains activated CD8+ T cells flowing through it. This retention is mediated mostly by hepatic ICAM-1 on Kupffer cells, and a proportion of the retained CD8+ T cells are undergoing apoptosis in the liver. Current work is focusing on the fate of activated CD8+ T cells when specific peptide is present in the liver, and also the ability of the liver to prime naive CD8+ T cells.