REJECTION MECHANISM AND IMMUNOSUPPRESSIVE STRATEGY OF SMALL BOWEL TRANSPLANTATION.

P38丝裂原活化蛋白激酶(MAPK)是一种应激激活的酶，负责传递炎症信号。在CD8+T淋巴细胞上，p38的表达与细胞毒活性有关。在细胞凋亡信号转导通路中，p38是由肿瘤坏死因子-α激活的，激活p38可诱导细胞凋亡。方法：研究方法。行异位小肠移植(SBT)。第一组。LEW→LEW(n=3)，第2组。BN→LEW(n=5，不治疗)，第3组，BN→LEW(n=3，FK5060.5 mg/kg，i.m.7d)。第4组BN→Lew(n=3)，抗α抗体1.0 mg/kg，静注。观察组织学、细胞凋亡、p38和磷酸化p38的免疫染色，以及磷酸化p38的免疫印迹。结果。第1组移植后第7天组织病理学改变，第2组出现中度至重度排斥反应，第3、4组移植后第7天出现轻、中度排斥反应。2组移植物CD8a/p38双阳性细胞较3组明显增多。经Mann-Whitney U检验，10hpF组TUNEL阳性细胞数(9.4±3.6)个明显多于组1(0.7±0.6)个(p=0.024)。第4组阳性细胞数(4.3±1.5)较第2组明显减少(p=0.047)。四组间p38表达细胞数差异无统计学意义。在磷酸化p38的表达上，第2组阳性细胞数明显多于第4组。免疫印迹法检测到排斥反应中，第2组的免疫反应条带比第4组强。由于同种异体移植排斥反应时的浸润性细胞主要表达磷酸化的p38，FK506和抗肿瘤坏死因子抗体联合治疗可能通过抑制p38的激活而取得成功。

The p38 mitogen-activated protein kinase (MAPK) is a stress-activated enzyme responsible for transducing inflammatory signals. On CD8+ T lymphocytes, p38 expression correlates with cytotoxic activity. Concerning apoptotic signaling pathways, p38 is activated by TNF-α and activation of p38 may induce apoptosis. Methods. Heterotopic small bowel transplantation (SBT) was performed. Group1. LEW → LEW (n=3), Group2. BN → LEW (n=5, no treatment), Group3, BN → LEW (n=3, FK506 0.5 mg/kg, i.m.for 7 days). Group4 BN → LEW (n=3, anti-TNF-α antibody ; 1.0mg/kg, i.p.injection at SBT). Histology, apoptosis, immunostaining of p38 and phosphospecific p38, and Western blot of phosphospecific p38 were examined. Results. The histopathologic findings of Group 1 on day 7 after transplantation, moderate to serve rejection was observed in Group 2. On the other hand, Group 3 and 4 on day 7 after transplantation showed mild to moderate rejection. The graft infiltrating CD8a/p38-double positive cells in Group 2 significantly increased compared with Group3. Concerning TUNEL-positive cells 10 HPF by Mann-Whitney U-test, there were more positive cells in Group 2 (9.4±3.6) than in Group 1 (0.7±0.6) (p=0.024). However, the number of positive cells in Group 4 (4.3±1.5) decreased significantly compared with Group 2 (p=0.047). There was no significant difference in the number of cells expressing p38 among four groups. In expression of phosphospecific p38, the numbers of positive cells in Group 2 seemed like more than that in Group 4. In the western blotting of phosphospecific p38 in rejecting allografts, immunoreactive bands in Group 2 were detected stronger than that in Group 4. Conclusions. Since the infiltrating cells at allograft rejection would predominantly express phosphospecific p38, combined FK506 and anti-TNF antibody therapy might success by suppressing the activation of p38.