Inhibition of Rejection Reaction by Modulating Actions of Adhesion Molecules on Sinusoidal Endothelial Cells in Rat Liver Allograft.

通过调节粘附分子对大鼠同种异体肝窦内皮细胞的作用来抑制排斥反应。

• 批准号: 05670509
• 负责人: YAMADA Shinwa
• 金额: $ 1.34万
• 依托单位: University of Occupational & Environmental Health (U.O.E.H.)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670509/
• 关键词: liver transplant; ischemia-reperfusion injury; adhesion molecule; neutrophil; endothelial injury; platelet; interleukin-8; hepatocyte growth factor

In this study we have investigated into roles of adhesion molecules and chemokines in rejection reaction. It is thought from a therapeutic point of view that there are two important phases ; neutrophil-adhesion to the endothelial cells immediately after reperfusion, and T cell-adhesion in acute rejection.I.Hepatic Injury after Ischemia-Reperfusion1.in vitroWhen rat liver was exposed to ischemia-reperfusion, serum IL-8 levels were immediately elevated and peaked at 6 hr after the reperfusion. The elevation was completely inhibited by inactivation of Kupffer cells.IL-8 mRNA was detected by Northern blot in the Kupffer cells isolated from the rat liver after the reperfusion, but was not detected in the control. These findings imply that IL-8 was derived from the activated Kupffer cells.2.in vitroIt has been reported that platelet plays an important role in hepatic injury after reperfusion. Thus in an in vitro study a possible role of platelet in neutrophil-adhesion was investigated. It wa … More s demonstrated that in an early phase of inflammation platelet stimulated by thrombin adhered to unstimulated endothelial cells (HUVEC) via Gp IIb/IIIa, and thereafter neutrophils were tethered by P-selectin on the platelet. The similar experiment using sinusoidal endothelial cells is under consideration.II.Possible roles of hepatocyte growth factor (HGF) in rejection reaction of rat liver allograftWe have demonstrated in an in vitro study that HGF promotes adhesion and migration of CD4 memory T-cells, and have proposed that it may contribute to induction of T cell-infiltration in the liver. Thus, we evaluated HGF level in the serum and the liver during the process of rejection reaction of rat liver allograft (ACI-Lewis), as comparing with those of donor specific tolerant (DST) group as the control. Serum HGF levels were significantly increased in DST as compared with those of the rejected group.In the liver of DST group, HGF was strongly expressed in the mononuclear cells in the portal areas, and there was infiltation of CD4 T-cells in the hepatic lobule. On the other hand, the liver of the rejected group showed HGF expression scattering in the hepatic lobules and the portal area surrounding the bile ductule. These results suggested possible roles of HGF in rejection reaction as follows : (1) it promotes hepatocyte regeneration (2) it induces CD4 T-cell migration in the liver (3) it stimulates proliferation of bile ductule cells. Less

在本研究中，我们探讨了黏附分子和趋化因子在排斥反应中的作用。从治疗的角度来看，大鼠肝脏缺血再灌注后，中性粒细胞与内皮细胞的黏附和急性排斥反应中T细胞的黏附是两个重要的阶段。1.大鼠肝脏缺血再灌流后的肝损伤。再灌注后分离的Kupffer细胞经Northern印迹法检测到IL-8的表达，而对照组未检测到IL-8的表达。这些结果提示IL-8来源于激活的Kupffer细胞。2.体外研究表明，血小板在再灌注后肝损伤中起重要作用。因此，在体外研究中，我们研究了血小板在中性粒细胞黏附中的可能作用。IT Wa…S进一步证明，在炎症早期，凝血酶刺激的血小板通过GP IIb/IIIa与未刺激的内皮细胞黏附，之后中性粒细胞被血小板上的P-选择素所束缚。利用肝窦内皮细胞进行的类似实验正在考虑中。II.肝细胞生长因子(HGF)在大鼠肝移植排斥反应中的可能作用我们在体外研究中证明了HGF促进CD4记忆T细胞的黏附和迁移，并提出它可能有助于诱导T细胞在肝脏中的渗透。因此，我们评估了大鼠肝移植排斥反应(ACI-Lewis)过程中血清和肝脏中HGF的水平，并与供体特异性耐受(DST)组进行了比较。DST组大鼠血清HGF水平明显高于排斥组，肝门管区单个核细胞HGF强阳性表达，肝小叶有CD4T细胞浸润。排斥组肝组织HGF表达呈散在分布于肝小叶和胆管周围的汇管区。这些结果提示HGF在排斥反应中可能的作用如下：(1)促进肝细胞再生；(2)诱导CD4T细胞在肝脏内迁移；(3)促进胆管细胞增殖。较少

项目成果

Tanaka,Y.: "T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1β." Nature. 361. 79-82 (1993)

Tanaka, Y.：“蛋白聚糖固定的细胞因子 MIP-1β 诱导的 T 细胞粘附。” Nature 361. 79-82 (1993)

Yamada,S.: "Evidence for enhanced secretory function of hepatic macrophages after long-term ethanol feeding in rats." Liver. 11. 220-224 (1991)

Yamada,S.：“长期喂食乙醇后大鼠肝巨噬细胞分泌功能增强的证据。”

Yamada, S., Mochida, S., Ohno, A., Hirata, K., Ogata, I., Ohta, Y., Fujiwara, K.: "Evidence for enhanced secretory function of hepatic macrophage after long-term ethanol feeding in rats." Liver. 11. 220-224 (1991)

Yamada, S.、Mochida, S.、Ohno, A.、Hirata, K.、Ogata, I.、Ohta, Y.、Fujiwara, K.：“长期乙醇喂养后肝巨噬细胞分泌功能增强的证据

Mori, N., Yamashita, U., Tanaka, Y., Nakata, K., Oda, S., Morimoto, I., Eto, S.: "Interleukin-4 induces proliferation of adult T-cell leukemia cells." Eur.J.Haematol.50. 133-140 (1993)

Mori, N.、Yamashita, U.、Tanaka, Y.、Nakata, K.、Oda, S.、Morimoto, I.、Eto, S.：“Interleukin-4 诱导成人 T 细胞白血病细胞增殖。”

桃坂泰寛: "C型慢性肝炎に対するインターフェロン療法の有効性の早期予測因子としての血清ICAM-1レベルの有用性" 肝臓. 35. 568-569 (1994)

Yasuhiro Momosaka：“血清 ICAM-1 水平作为干扰素治疗慢性丙型肝炎有效性的早期预测因子的有用性”，肝脏，35. 568-569 (1994)。