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

Abstract Background & Aims : 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 predominantly produced by hepatocytes, which rises during acute phase responses, is lost in patient's stool due to gastrointestinal GVHD, and its augmentation was found to attenuate GVHD. Here, we explore the effect of immunosuppressive drugs on hepatocyte production of AAT and intestinal epithelial gap repair. Approach : 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 patients, obtained 14 days post-transplantation, predating the diagnosis of GVHD (n=6) were examined for re-epithelialization, with added clinical-grade AAT. Results : Rapamycin compromised AAT production under inflammatory conditions. Mycophenolate mofetil and cyclosporin A inhibited re-epithelialization; AAT minimized the effect of cyclosporin A. Patient sera displayed superior gap repair with exogenous AAT. Conclusions : Functional insufficiency in circulating AAT may be the result of drug toxicities leading to ineffective gut re-epithelization and compromised gut lining. Taken together, our data strengthen the rationale for incorporating AAT augmentation therapy into immunosuppressive treatment protocols.