Local immunomodulation as a new approach to ABO-incompatible liver transplantation

局部免疫调节作为 ABO 不相容肝移植的新方法

• 批准号: 14571155
• 负责人: TANABE Minoru
• 金额: $ 2.56万
• 依托单位: KEIO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571155/
• 关键词: ABO-blood type incompatibility; liver transplantation; rejection; rat model

ABO-incompatibility is usually regarded as contraindication of liver transplantation, because preformed antibodies to donor-blood group antigen induce severe rejection with a high-rate of bile duct and vascular complications. The aim of this study is to investigate the effects of graft immunomodulation on humoral rejection in rat liver transplant model. We established presensitized recipients (Lewis) by donor-strain (BN) skin grafting. These recipients reject the liver graft from the BN rat within 30 days by humoral rejection. Pathologic findings of the rejected liver showed wide spread hemorrhagic necrosis with intra-organ thrombosis, which is similar to those seen in the failed graft after clinical ABO-incompatible liver transplantation. We developed new technique of continuous intra-portal drug infusion in the rat model, using osmotic pump. The immunomodulatory agents, including prostaglandin E1, budesonide, and gabexate mesilate, was infused intraportally for 14 days after transplantation. Prostaglandin E1 improves microcirculation through vasodilating effect and inhibits platelet aggregation. Budesonide is the newly developed steroid which is completely metabolyzed through portal circulation. Gabexate mesilate, a protease inhibitor commonly used for systemic DIC, inhibits platelet aggregation, thrombin, and other coagulation factors as well. These local immunomodulation improved the degree of rejection, and tended to prolong the recipient survival. Our results shows that this new concept of intra-portal infusion therapy has a strong potential to break through the ABO-blood group barriers in liver transplantation, and to provide much greater opportunity for liver transplantation for these patients.

ABO血型不合通常被认为是肝移植的禁忌症，因为针对供体血型抗原的预制抗体会引起严重的排斥反应，并伴有高比例的胆管和血管并发症。本研究的目的是探讨移植物免疫调节对大鼠肝移植模型体液排斥的影响。我们通过供体株（BN）植皮建立了预敏化受体（Lewis）。这些受体在 30 天内通过体液排斥排斥来自 BN 大鼠的肝移植物。被排斥的肝脏的病理结果显示广泛的出血性坏死并伴有器官内血栓形成，这与临床ABO不合肝移植后失败的移植物中所见的情况相似。我们开发了使用渗透泵在大鼠模型中连续门脉内药物输注的新技术。移植后门静脉内输注免疫调节剂，包括前列腺素 E1、布地奈德和甲磺酸加贝酯 14 天。前列腺素E1通过血管舒张作用改善微循环并抑制血小板聚集。布地奈德是新开发的类固醇，通过门循环完全代谢。甲磺酸加贝酯是一种常用于治疗全身性 DIC 的蛋白酶抑制剂，还可抑制血小板聚集、凝血酶和其他凝血因子。这些局部免疫调节改善了排斥程度，并倾向于延长受体的生存期。我们的研究结果表明，这种新概念的门静脉输注治疗具有突破肝移植中ABO血型障碍的强大潜力，为这些患者提供更大的肝移植机会。

项目成果

Tanabe M, Shimazu M, Wakabayashi G, Hoshino K, Kawachi S, Morikawa Y, Kitajima M.: "Living-donor liver transportation : Current efforts to expand the donor pool."Annals of European Academy of Sciences. 22-31 (2003)

Tanabe M、Shimazu M、Wakabayashi G、Hoshino K、Kawachi S、Morikawa Y、Kitajima M.：“活体供体肝脏运输：当前扩大供体库的努力。”欧洲科学院年鉴。

Yamamura T, Ueda M, Psarras K, Suwa T, Watanabe Y, Kameyama N, Tanabe M, Imamura H.: "Immunosuppressive and anticancer effect of a mammalian ribonuclease that targets high-affinity interleukin-2-receptors."Eur J Surg. 168. 49-54 (2002)

Yamamura T、Ueda M、Psarras K、Suwa T、Watanabe Y、Kameyama N、Tanabe M、Imamura H.：“针对高亲和力白细胞介素 2 受体的哺乳动物核糖核酸酶的免疫抑制和抗癌作用。”Eur J Surg。

Tanabe M, et al.: "Intra-portal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation."Transplantation. 73. 1959-1961 (2002)

Tanabe M 等人：“门静脉内输注疗法是成人 ABO 不相容肝移植的一种新方法。”移植。

Morisue A, Wakabayashi G, Shimazu M, Tanabe M, Mukai M, Matsumoto K, Kawachi S, Yoshida M, Yamamoto S, Kitajima M.: "The role of Nitric Oxide after a short period of liver ischemia-reperfusion."J Surg Res. 109. 101-109 (2003)

Morisue A、Wakabayashi G、Shimazu M、Tanabe M、Mukai M、Matsumoto K、Kawachi S、Yoshida M、Yamamoto S、Kitajima M.：“一氧化氮在短期肝脏缺血再灌注后的作用。”J Surg

Shimazu M, Tanabe M, et al.: "Living donor liver transplantation across the ABO blood groups : A novel strategy using intra-portal infusion therapy"Transplantation. 74. 25 (2002)

Shimazu M、Tanabe M 等人：“跨 ABO 血型的活体肝移植：使用门静脉内输注疗法的新策略”移植。