Fujisawa Kenji, Saito Shinya, Okada Yutaka, Fujiwara Toshiyosi, Yagi Takahito, Iwagaki Hiromi, Tanaka Noriaki
Department of Gastroenterological Surgery and Transplant, Okayama University Graduate School of Medicine and Dentistry, Okayama city, 700-8558 Japan.
Cell Transplant. 2003;12(4):379-87. doi: 10.3727/000000003108746920.
Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the upregulation of proinflammatory activity that leads to destruction of allogeneic hepatocytes following transplantation. Th2-type cytokines. such as IL-10, have immune regulatory function. The aim of this study was to determine the antirejection efficacy of allogeneic hepatocytes with spheroidal shape (spheroids) genetically modified with viral IL-10 (vIL-10). Allogeneic hepatocyte spheroids, transferred vIL-10 gene by using adenovirus as the vector, were transplanted into the spleen of Nagase's analbuminemic rats (NAR). NAR transplanted with vIL-10-transfected hepatocytes showed an abrupt rise in serum albumin levels that peaked on day 7 and remained at high levels up to day 21 after transplantation. The peak level of albumin on day 7 in vIL-10-transfected NAR was eminently higher than that in nontransfected NAR. Histopathological analysis revealed that in nontransfected NAR hepatocyte spheroids were more or less rejected on day 4, and, in contrast, vIL-10-transfected spheroids were still not rejected on day 14. This protective effect correlated with sustained high vIL-10 level in the splenic vein in NAR transplanted with vIL-10-transfected hepatocyte spheroids, suggesting that vIL-10 secreted from the transplanted hepatocytes induced an active suppression of allogeneic response. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent allogeneic response in hepatocyte transplantation.
Th1细胞活化和细胞因子产生会改变Th1和Th2之间的平衡，有利于促炎活性的上调，这会导致移植后同种异体肝细胞的破坏。Th2型细胞因子，如IL-10，具有免疫调节功能。本研究的目的是确定经病毒IL-10（vIL-10）基因修饰的球形同种异体肝细胞（球体）的抗排斥效果。通过使用腺病毒作为载体转染vIL-10基因的同种异体肝细胞球体被移植到长谷白蛋白缺乏大鼠（NAR）的脾脏中。移植了vIL-10转染肝细胞的NAR血清白蛋白水平急剧上升，在第7天达到峰值，并在移植后第21天一直保持在高水平。vIL-10转染的NAR在第7天的白蛋白峰值水平明显高于未转染的NAR。组织病理学分析显示，在未转染的NAR中，肝细胞球体在第4天或多或少被排斥，相反，vIL-10转染的球体在第14天仍未被排斥。这种保护作用与移植了vIL-10转染肝细胞球体的NAR脾静脉中持续高的vIL-10水平相关，表明移植肝细胞分泌的vIL-10诱导了对同种异体反应的主动抑制。本研究提供了证据支持使用vIL-10基因疗法预防肝细胞移植中同种异体反应的可能性。
