Promising clinical outcomes in early liver transplantation (ELT) for severe alcoholic hepatitis raise new questions: Does chronic and active alcohol use impact allograft rejection after ELT? Is a living donor or reduced sized liver suitable for ELT? How early is too early to have an ELT? Is there a biologic basis why the majority of SAH patients (>75%) without pre-transplant abstinence have no alcohol relapse 2-3 years after ELT? These questions can be approached in animal models of liver transplantation. In the last funding period, we established a rat liver transplantation model in which a DA or Lewis rat liver is transplanted into Lewis recipients fed with alcohol vs a control diet for 8 weeks. We found chronic alcohol exposure not only reduced the recipient survival times significantly, but also reduced the efficacy of immunosuppressive therapy. Both chronic alcohol exposure and immunosuppressive therapy inhibited liver regeneration following reduced sized (50%) liver transplantation; Searching for an underlying mechanism, we found evidence of dramatically increased neutrophilic infiltration in liver allografts of alcohol fed recipients early following transplantation and chronic alcohol exposure produced excessive priming of the neutrophil respiratory burst in circulating leukocytes suggesting priming of the neutrophil respiratory burst by alcohol exposure may play an important role in liver allograft rejection/oxidative injury and regeneration. A striking finding is that a new stem cell mobilizing therapy (MRG-001) not only improved survival of alcohol fed recipients (100%) following allogeneic liver transplantation, but also promoted liver allograft regeneration. Based on these findings, we hypothesize that chronic and active alcohol abuse impacts innate immunity especially neutrophils, and infiltration of alcohol dysregulated neutrophils promotes liver allograft rejection/damage following transplantation. Further, current immunosuppressive therapy is ineffective in preventing neutrophil infiltration and inhibits liver regeneration following reduced sized graft transplantation. We propose that short-term abstinence or a new bone marrow stem cell/immunoregulatory cell mobilizing therapy (MRG-001) may eliminate alcohol dysregulated neutrophils/innate immunity and promote allograft acceptance and regeneration in alcohol fed recipients. In addition, transplantation of a genetically different liver may alter alcohol use behavior. The following aims test these hypotheses. Our proposed studies involve: 1) evaluating the impact of alcohol dysregulated neutrophils on allograft rejection and oxidative damage and to determine if short- term abstinence or MRG-001 pretreatment eliminates alcohol dysregulated neutrophils following LT, 2) developing a strategy for living donor ELT to promote regeneration and tolerance of small liver allografts, and 3) determining if transplantation of a genetically different liver to alcohol-preferring (P) rats alters al...