Effect of Chronic Alcohol Use on Alloimmunity.

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): The need for orthotopic liver transplantation (OLT) for the treatment of alcohol induced chronic liver disease (ALD) in the US outnumbers the availability of donor livers. Eligibility for OLT amongst chronic alcoholics requires a 6-months period of sobriety. This six-month rule is problematic for patients with severe alcoholic hepatitis and a high model for end-stage liver disease (MELD) score, as the mortality risk is within this 6-month period. Cell replacement therapy (CRT) using liver cells (hepatocytes), has been considered as a short-term liver support until a suitable liver is available, and several preclinicl and clinical studies of acute or chronic liver failure have demonstrated that hepatocyte CRT can support liver function and improve survival in mice and in patients. A significant barrier to this therapy, however, is immunological rejection, which is largely mediated by a T cell-dependent pathway. In immunocompetent transplant recipients, immunosuppressive drugs are required to prevent transplant rejection. Evidence from alcohol research suggests ethanol consumption may diminish immune function resulting in reduced rejection following liver or hepatocyte transplantation. The underlying mechanism for this observation remains unanswered. Some studies suggest chronic alcohol consumption leads to T cell lymphopenia, which in turn induces antigen-independent expansion of memory-like T cells, termed homeostatic proliferation. Whether these events directly contribute to immunosuppression remains unanswered, although we believe these events may be linked to premature immune aging and cellular senescence. Thus, the long-term objective of this study is to test the hypothesis that chronic alcohol use accelerates T cell aging and impairs T cell function, thereby reducing T cell mediated graft injury and necessitating less immunosuppression after CRT and OLT for individuals with ALD. To test this hypothesis, I propose two Aims: in the First Aim I will characterize the effect of chronic ethanol consumption on T cell function and aging, and determine if these effects on T cells are reversible following ethanol withdrawal. In the Second Aim I will use a chronic alcohol mouse model to determine whether transplanted hepatocytes have improved graft survival compared to hepatocytes transplanted into ethanol free controls, and will evaluate the effect of chronic alcohol consumption on T cell alloimmunity. The findings from this study will have multiple impacts on public health. They will: 1) define the impact of chronic ethanol consumption on T cell immune responses, 2) assess impaired T cell function in a chronic alcohol model following hepatocellular transplantation, 3) provide evidence for using reduced levels of immunosuppressive drugs for CRT in patients with ALD, and 4) provide a potential treatment strategy for individuals with a high MELD score and for patients who have stopped drinking and are working towards sobriety, or have been sober for 6 month but are awaiting OLT.