Immunosuppressive Drugs Alter α1-Antitrypsin Production in Hepatocytes: Implications for Epithelial Gap Repair

Immunosuppressive drugs are an inherent component of hematopoietic stem cell transplantation (HSCT) for the prevention of acute graft-versus-host disease (GVHD). Circulating α1-antitrypsin (AAT), a serine-protease inhibitor produced predominantly by hepatocytes that rises during acute phase responses, is lost in patient's stool due to gastrointestinal GVHD, and its augmentation has been found to attenuate GVHD. Here we explored the effect of immunosuppressive drugs on hepatocyte production of AAT and intestinal epithelial gap repair. The effect of commonly used immunosuppressants on AAT production was examined in vitro using HepG2 cells and primary mouse hepatocytes, and their impact on human intestinal epithelial cell line gap repair was evaluated. Sera from 12 allogeneic HSCT recipients, obtained at 14 days post-transplantation, predating the diagnosis of GVHD (n = 6), were examined for reepithelialization, with added clinical-grade AAT. Rapamycin compromised AAT production under inflammatory conditions. Mycophenolate mofetil and cyclosporine A (CSA) inhibited reepithelialization; AAT minimized the effect of CSA. Patient sera displayed superior gap repair with exogenous AAT. Functional insufficiency in circulating AAT may be the result of drug toxicities leading to ineffective gut reepithelization and compromised gut lining. Taken together, our data strengthen the rationale for incorporating AAT augmentation therapy into immunosuppressive treatment protocols.