THE IMMUNOLOGICAL HYPORESPONSIVENESS AND DONOR CELL PERSISTENCE IN HOST LIVER AFER PORTAL VENOUS INNOCULATION

门静脉接种后宿主肝脏的免疫低反应性和供体细胞的持久性

• 批准号: 06671205
• 负责人: TANAKA Noriaki
• 金额: $ 1.09万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671205/
• 关键词: Transplantation; Tolerance; Portal venous; Liver; Kupffer cell; 移植免疫; microchimerism; キメリズム; 白血球; ノイラミニダーゼ; 門脈内注入; ラット

The immunosuppressants used now a days in transplantation have not only incomplete inhibition of the rejection but also some incidense of complications such as oppotunistic infection, malignansies etc. hypo- or no response to the antigen is called immunological tolerance, which induces low or no incidense of rejection and results from the reduction of immunosuppressants. Although portal venous inoculation of donor antigen was reported to induce donor-specific hyporesponsiveness and prolongation of the grafts in animal models, the mechanism of the portal tolerance has not been clearly understood. In this study, we investigated the corelation between donor cell persistence in host liver and the suppression of donor-specific mixed lymphocyte reaction. The sequential changes in fluoresence labeled donor cells inoculated via the portal (PV group) or peripheral (IV group) vein were examined using fluoresence microscopy and flow cytometory. The fluorescent positive cells were mainly located i … More n the sinusoid of periportal and midzonal area of hepatic lobules, and several and a few positive cells per hepatic lobules on day 3 and 7, respectively. The number of fluoresent positive cells was seen impresively greater in PV group than in IV group on day 3 and 7. More quantitatively, flow cytometric analysis of the isolated hepatic non-parenchymal cells revealed that the percentage of fluoresent positive cells were significantly higher in PV group than in IV group on day 3, but no significant difference could not be observed between both groups on day 7. MLR was significantly suppressed on day 3 and slightly on day 7 in PV group, comparing with slight MLR suppression only on day 3 in IV group. Gadolinium chloride (Gd) which inhibits the phagocytic activity of Kupffer cell was given intravenously to host rats on 2 consecutive days before portal venous inoculation (GdPV group). In GdPV group high percentage of donor cell persistence and the suppression of MLR by portal venous inoculation were lost to the low level of IV group on day 3. Oral tolerance, which induces the suppression of anbibody production and cellular immunity in an antigen specific fashion, was studied to be able to apply to the transplantation tolerance. Intra-jejunal administration of donor spleen cells (5×10ィイD17ィエD1/day×5days) through the jejunostomy tube was proud to suppress the MLR and foot pad reaction in a donor specific manner, and significantly prolonge the cardiac allograft survival. Gd administration lost these donor-specific immunological hyporesponsiveness and the prolongation of gaft survival. These results indicates that high percentage of persistent donor cells in the host liver was good corelation with the suppression in donor-specific MLR and Kupffer cells play a crucial role in the portal tolerance. Less

目前移植中使用的免疫抑制剂不仅不能完全抑制排斥反应，而且还会引起机会性感染、恶性肿瘤等并发症。对抗原的低反应或无反应称为免疫耐受，它是由于减少免疫抑制剂的使用而引起的低或无排斥反应。虽然门静脉接种供体抗原在动物模型中被报道诱导供体特异性低反应性和移植物的延长，但门静脉耐受的机制尚未被清楚地理解。在这项研究中，我们探讨了供体细胞在宿主肝脏中的持久性和供体特异性混合淋巴细胞反应抑制之间的相关性。应用荧光显微镜和流式细胞术检测经门静脉（PV组）或外周静脉（IV组）接种的荧光标记供体细胞的时序性变化。荧光阳性细胞主要分布于 ...更多信息 第3天和第7天，门静脉周围血窦和肝小叶中间区可见少量阳性细胞。第3、7天PV组荧光阳性细胞数明显多于IV组。更定量地，对分离的肝非实质细胞的流式细胞术分析显示，在第3天，PV组的荧光阳性细胞百分比显著高于IV组，但在第7天，两组之间未观察到显著差异。PV组MLR在第3天明显抑制，第7天轻度抑制，而IV组仅在第3天轻度抑制。GdPV组在门静脉接种前连续2天静脉注射抑制枯否细胞吞噬功能的氯化钆（Gd）。在GdPV组中，高百分比的供体细胞存留和门静脉接种对MLR的抑制在第3天丧失至IV组的低水平。口服耐受以抗原特异性方式诱导抗体产生和细胞免疫的抑制，研究表明口服耐受能够应用于移植耐受。经空肠吻合管空肠内输注供者脾细胞（5×10 ~（17）× 10 ~（17）D_1/天× 5天），可抑制供者特异性的MLR和足垫反应，显著延长移植心脏存活时间。钆给药可使这些供者特异性免疫低反应消失，并延长移植物存活时间。这些结果表明，供体细胞在宿主肝脏中的高比例持续存在与供体特异性MLR的抑制有良好的相关性，Kupffer细胞在门脉耐受中起重要作用。少

项目成果

Isido, N., Matsuoka J., Nakagawa, K., Matsumoto, T., and Tanaka, N.,: "Induction of hyporesponsiveness and prolongation of cardiac allograft survival after jejunal administration of donor splenocytes and its abrogation by administration of gadolinium."Tra

Isido, N.、Matsuoka J.、Nakakawa, K.、Matsumoto, T. 和 Tanaka, N.：“空肠给予供体脾细胞后诱导低反应性并延长心脏同种异体移植物的存活率，并通过给予钆消除这种情况。

Ishido, N., Matsumoto, T., Matsuoka, J., Nakagawa, K., Haisa, M., Saito, S., Yagi, T., Oishi, M., Ishikawa, T., Fujisawa, K., Matsuda, H., Okada, Y., Endo, A., and Tanaka, N.,: "Can intraoperative inoculation of donor splenocytes via the portal vein prolo

石户，N.，松本，T.，松冈，J.，中川，K.，Haisa，M.，斋藤，S.，八木，T.，大石，M.，石川，T.，藤泽，K.，

Ishido,N.: "Can intraoperative inoculation of donor splenocytes via the portal vein prolong allograft survival?"Transplantation Proceedings. 30. 3883-3884 (1998)

Ishido,N.：“术中通过门静脉接种供体脾细胞可以延长同种异体移植物的存活吗？”移植论文集。

Uda, M., Fujiwara, T., Kusaka, S., Matsumoto, T., Tanaka, N., and Orita, K.,: "Donor specific inhibitory factor induced by portal venous inoculation with ultraviolet-B irradiated spleen cells in nonhuman primates."Transplantation Proceedings.. 26. 1848-18

Uda, M.、Fujiwara, T.、Kusaka, S.、Matsumoto, T.、Tanaka, N. 和 Orita, K.：“门静脉接种紫外线 B 照射的脾细胞诱导的供体特异性抑制因子

Uda,M.: "Donor specific inhibitory factor induced by portal venous inoculation with ultraviolet-B irradiated spleen cells in nonhuman primates"Transplantation Proceedings. 26. 1848-1850 (1994)

Uda,M.：“在非人类灵长类动物中用紫外线 B 照射的脾细胞门静脉接种诱导的供体特异性抑制因子”移植论文集。