*Purpose: Alcoholic liver disease is the leading indication for liver transplantation in the United States, and patients are increasingly transplanted without the traditional six month period of pre-transplant sobriety. As chronic alcohol consumption is associated with significant alterations in immune function, we sought to evaluate the impact of chronic ethanol exposure on alloimmunity using a murine skin graft model.

*Methods: C57BL/6 mice (B6) were randomized to receive either ethanol (20%) or water over a 12-week period. Female B6 mice were then grafted with skin from male B6 donors. We additionally utilized a clinically-relevant fully allogeneic transplant model using BALB/c => B6 skin graft recipients treated with costimulatory blockade (CTLA-4 Ig⁺ anti-CD40L on post-transplant day 0, 2, 4 and 6). To evaluate the durability of the chronic ethanol-induced changes in alloimmunity, B6 mice treated with 12 weeks of ethanol were given a “washout” period of either 2 weeks or 2 months of water alone prior to receiving a BALB/c skin graft under costimulatory blockade. Finally, we probed potential mechanisms by which chronic alcohol use could prolong graft survival. BALB/c=>B6 skin graft recipients were sacrificed on POD14 and splenocytes were phenotyped by flow cytometry.

*Results: Ethanol-exposed female mice with male donors had significantly longer graft survival with a median survival time (MST) of >60 days compared to 35.5 in water controls (p=0.041). We found similar survival benefits in the Balb/c to B6 model where again chronic ethanol exposure substantially prolonged graft survival (MST 29 vs. 21 days, p= 0.028). Compared to alcohol-free controls, there was a trend towards increased survival even after 2 weeks of washout (MST= 31 vs. 24 days, p= 0.156) that disappeared completely by 2 months of washout (MST= 21 vs. 24.5 days, p= 0.952). Chronic ethanol exposure significantly increased the frequency of FoxP3⁺ Tregs (16.7% vs. 6.4% of CD4⁺ T cells, p= 0.001), potentially explaining the prolonged graft survival observed after chronic alcohol use.

*Conclusions: Chronic alcohol use prolongs transplant survival in both minor antigen mismatch and fully allogeneic transplant models, potentially due to expansion of graft-protective Tregs. This finding is clinically relevant given the increasing proportion of human transplant patients with recent heavy alcohol use at the time of transplant, potentially justifying reduction of early immunosuppression in these patients to protect them against opportunistic infection given that rejection responses may be suppressed in these patients.

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