HCV-Induced Immune Responses Influence the Development of Operational Tolerance After Liver Transplantation in Humans
HCV-Induced Immune Responses Influence the Development of Operational Tolerance After Liver Transplantation in Humans
复制标题
DOI：
10.1126/scitranslmed.3008793
复制
发表时间：
2014-06-25
影响因子：
17.1
通讯作者：
Sanchez-Fueyo, Alberto
中科院分区：
文献类型：
--
作者：
Bohne, Felix;Londono, Maria-Carlota;Sanchez-Fueyo, Alberto
病原体诱导的免疫应答阻止实验动物模型中移植耐受的建立。这种情况是否也发生在人类身上尚不清楚。慢性丙型肝炎病毒（HCV）感染的肝移植受者手术耐受性的发展使我们能够解决这个问题。我们在HCV感染的成人肝脏受者中进行了一项免疫抑制撤销的临床试验，以阐明（i）在存在持续炎症反应的情况下建立同种异体移植物耐受的机制，以及（ii）抗HCV异源免疫反应是否影响这种现象。在34例入组的肝移植受者中，17例患者（50%）成功停药。耐受性与肝内I型干扰素和免疫调节基因的过度表达以及PD 1/CTLA 4/2B 4阳性HCV特异性循环CD 8（+）T细胞的扩增有关。这些结果在免疫抑制停止前就已经存在，并且对HCV感染具有特异性。与此相反，HCV诱导的促炎基因表达的幅度和抗HCV效应T细胞反应的广度并不影响药物戒断结果。我们的数据表明，在人类中，持续的病毒感染发挥免疫调节作用，可能有助于抑制同种异体免疫反应，并不一定排除同种异体移植耐受的发展。
Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.