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.

中文翻译：

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免疫抑制药物改变肝细胞中α1-抗胰蛋白酶的产生：对上皮间隙修复的影响。

免疫抑制药物是造血干细胞移植（HSCT）的固有成分，可预防急性移植物抗宿主病（GVHD）。循环α1-抗胰蛋白酶（AAT）是一种主要由肝细胞产生的丝氨酸蛋白酶抑制剂，在急性期反应期间会上升，由于胃肠道GVHD而在患者的粪便中丢失，并且发现其增强会减弱GVHD。在这里，我们探讨了免疫抑制药物对AAT肝细胞产生和肠上皮间隙修复的影响。使用HepG2细胞和原代小鼠肝细胞在体外检查了常用免疫抑制剂对AAT产生的影响，并评估了它们对人肠上皮细胞系间隙修复的影响。移植后14天获得的来自12个同种异体HSCT受体的血清，在诊断为GVHD（n = 6）之前，对患者进行了再上皮化检查，并添加了临床级别的AAT。雷帕霉素在炎性条件下损害了AAT的产生。霉酚酸酯和环孢素A（CSA）抑制了上皮再形成；AAT最小化了CSA的影响。患者的血清显示出用外源性AAT进行的间隙修复效果更好。循环AAT的功能不足可能是药物毒性导致肠道再上皮无效和肠道内膜受损的结果。综上所述，我们的数据加强了将AAT增强疗法纳入免疫抑制治疗方案的理由。霉酚酸酯和环孢素A（CSA）抑制了上皮再形成；AAT最小化了CSA的影响。患者的血清显示出用外源性AAT修复间隙的效果。循环AAT的功能不足可能是药物毒性导致肠道再上皮无效和肠道内膜受损的结果。综上所述，我们的数据加强了将AAT增强疗法纳入免疫抑制治疗方案的理由。霉酚酸酯和环孢素A（CSA）抑制了上皮再形成；AAT最小化了CSA的影响。患者的血清显示出用外源性AAT进行的间隙修复效果更好。循环AAT的功能不足可能是药物毒性导致肠道再上皮无效和肠道内膜受损的结果。综上所述，我们的数据加强了将AAT增强疗法纳入免疫抑制治疗方案的理由。