Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain.
J Clin Invest. 2012 Jan;122(1):368-82. doi: 10.1172/JCI59411. Epub 2011 Dec 12.
Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation.
器官移植后，需要终身使用免疫抑制疗法来防止宿主免疫系统破坏移植物。这会导致严重的副作用，并增加受者的发病率和死亡率。在选定的移植受者中，已成功实现完全停止免疫抑制药物治疗，这为临床移植中获得操作性移植物耐受提供了原理证明。然而，与成功停药相关的移植物内分子途径尚未得到很好的定义。在这项研究中，我们分析了前瞻性多中心免疫抑制药物停药临床试验中入组的肝移植受者的连续血样和肝组织样本。在开始停药之前，操作性耐受和非耐受受者在调节铁稳态的基因在移植物内的表达上存在差异。此外，与非耐受受者相比，操作性耐受患者的血清铁调素和铁蛋白水平升高，肝细胞铁沉积增加。最后，肝组织基因表达测量在一组独立的患者中准确预测了免疫抑制停药的结果。这些结果表明，铁代谢在调节人类移植物同种免疫反应中起关键作用，并提供了一组生物标志物，可用于进行肝移植中的药物脱瘾试验。
