INDUCTION AND MAINTENANCE OF IMMUNOLOGICAL TOLERANCE IN REPEATED HEPATOCYTE TRANSPLANTATIONS FOR THE CONGENITAL HEPATIC ENZYME DEFICIENCY DISEASES

先天性肝酶缺乏症重复肝细胞移植中免疫耐受的诱导和维持

• 批准号: 12671191
• 负责人: ONODERA Kazuhiko
• 金额: $ 2.05万
• 依托单位: ASAHIKAWA MEDICAL COLLEGE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671191/
• 关键词: INTRASPLENIC HEPATOCYTE TRANSPLANTATION; RIB-5; 2; IMMUNOLOGICAL TOLERANCE

Major problem facing hepatocytes transplantation now is host sensitization to MHC antigens which were transplanted repeatedly because of a depletion of effects of previously transplanted hepatocytes. In this study, we investigated the usefulness of anti CD4 mAb, which had been proven to induce transplantation toleranse in sensitized rats.Allogeneic hepatocytes transplanted into the spleen were histologically rejected within several days when untreated with any immunosuppression (F344 to LEWS; 3-4 days, F344 to WKA; 1-2 days). However, administration of ciclosporine A achieved prolongation of hepatocytes survival (F344 to LEWS; > 3weeks, F344 to WKA; 3 〜 4days). On the other hand, no survival effect was obtained in the rats, which were treated with RIB-5/2 (a nondepleting CD4 mAb.) every day after the transplantation. Rejected hepatocytes showed unclear margin with a scanty cytoplasm and nuclear pyknosis or giant cell formation histologically, similar to that of untreated rats.Secondary hepatocytes transplantation from the same donor strain into the spleen 12 days after the first hepatocytes transplantation under the treatment with RIB-5/2, demonstrated no definite graft survival.According to these results, RIB-5/2 alone does not have immunosuppresed effects to the allogeneic hepatocytes transplantation, and probably can not induce toleranse to sensitized hosts in spite of the usage of this agent during the sensitization period. It seems that CD4^+ T cells and CD8^+ T cells independently work in hepatocellular allograft rejection, leading to no immune events associated with "infectious" toleranse.

目前肝细胞移植面临的主要问题是宿主对MHC抗原的致敏，因为先前移植的肝细胞的效应被耗尽而重复移植。在本研究中，我们研究了抗CD_4单克隆抗体的作用，它已被证明能诱导致敏大鼠的移植耐受，当未给予任何免疫抑制时，移植到脾脏中的同种异体肝细胞在几天内发生组织学排斥（F344对LEWS; 3-4天; F344对WKA; 1-2天）。然而，给予环孢素A可延长肝细胞存活时间（F344至LEWS; > 3周，F344至WKA; 3 ~ 4天）。另一方面，在用RIB-5/2（一种非消耗性CD 4 mAb）处理的大鼠中未获得存活效应。移植后的每一天。排斥的肝细胞在组织学上表现为边缘不清、细胞质稀少、核固缩或巨细胞形成，与未处理的大鼠相似。在第一次肝细胞移植后12天，在RIB-5/2处理下，从同一供体品系移植的第二次肝细胞移植到脾脏中，没有明确的移植物存活。根据这些结果，RIB-5/2单独应用对同种异体肝细胞移植无免疫抑制作用，即使在致敏期使用RIB-5/2，也可能不能诱导致敏宿主产生耐受。CD 4 ^+ T细胞和CD 8 ^+ T细胞在肝细胞移植排斥反应中似乎是独立发挥作用的，因此不存在与“感染性”耐受相关的免疫事件。

项目成果

Ana J Coito: "Fibronectir-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network Tolerant Transplant Recipients"American Journal of Pathology. 157・4. 1207-1218 (2000)

Ana J Coito：“Fibronectir-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network Tolerant Transplant Recipients”美国病理学杂志157・4（2000）。

COITO A. J., ONODERA K., ET AL.: "FIBRONECTIN-MONONUCLEA CELL INTERACTIONS REGULATE TYPE 1 HELPER T CELL CYTOKINE NETWORK IN TOLERANT TRANSPLANT RECIPIENTS"AMERICAN JOURNAL OF PATHOLOGY. VOL. 157, No. 4. 1207-1218 (2000)

COITO A. J.、Onodera K. 等人：“纤连蛋白-单核细胞相互作用调节耐受移植受者中的 1 型辅助 T 细胞细胞因子网络”美国病理学杂志。

Ana J.Coito: "Fibronectin-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network Tolerant Transplant Recipisents"American Journal of Pathology. 157・4. 1207-1218 (2000)

Ana J.Coito：“纤连蛋白-单核细胞相互作用调节 1 型辅助 T 细胞细胞因子网络耐受移植接受者”美国病理学杂志 157・4（2000 年）。

Ana J.Coito: "Fibronectin-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network Tolerant Transplant Recipients"American Journal of Pathology. 157(4). 1207-1218 (2000)

Ana J.Coito：“纤连蛋白-单核细胞相互作用调节 1 型辅助 T 细胞细胞因子网络耐受移植受者”美国病理学杂志。