Defining the role of antigen-specific T cell responses in NASH

Project Summary
Chronic liver diseases are a collection of disorders that result in significant morbidity and mortality worldwide.
The overwhelming burden of these diseases results in the liver being the second most transplanted organ. As
a result of a dramatic rise in the incidence of obesity and alcohol consumption, the rate of liver transplantation
continues to climb world-wide. Despite the significant impact of chronic liver disease on society, there are no
effective therapies to ameliorate disease outside of lifestyle modification and liver transplantation. Thus, a
more rigorous understanding of the mechanisms that drive the progression of chronic liver disease is required
to identify novel targets for therapeutic intervention. Our previous publication demonstrated a significant
accumulation of T lymphocytes in the liver of individuals with Non-Alcoholic Steatohepatitis (NASH)-induced
cirrhosis. However, the precise role of T cells in the progression of NASH has yet to be firmly established. The
preliminary studies presented in this application have identified a yet to be appreciated role for T cell activation
and clonal expansion during NASH. In this application we demonstrate that T cell clonal expansion is a
common event in both humans with NASH-induced cirrhosis and mice with NASH. These are the first studies
to identify T cell clonal expansions in the liver of humans and/or mice with NASH and link T cell activation and
function with NASH pathology. However, the exact antigenic cause of T cell activation or if these T cells are
inducing or suppressing disease progression is unknown. The studies in this application aim to answer these
two fundamental questions by defining (1) the timing of T cell clonal expansion in the liver during the
progression of NASH, (2) the antigens recognized by clonally expanded T cells, (3) the antigen presenting cell
(APC) that drives T cell clonal expansion, and (4) if eliminating T cell clonal expansion through depletion of
clonally expanded T cells or the APCs presenting antigens to these T cells results in prevention and/or
resolution of disease. Completion of these studies will provide a paradigm shift in our understanding of the
pathogenesis of NASH and will generate the tools necessary to define the role of T cells in the progression of
other chronic liver diseases.

Grant Number: 1R56DK135533-01A1
NIH Institute/Center: NIH
Principal Investigator: Matthew Burchill