Zhang J L, Yamaguchi Y, Mori K, Okabe K, Hidaka H, Ohshiro H, Uchino S, Ishihara K, Furuhashi T, Yamada S, Ogawa M
Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan.
J Surg Res. 2001 Apr;96(2):296-303. doi: 10.1006/jsre.2000.6065.
Serine protease inhibitors have profound suppressive effects on cellular and humoral immune responses. We investigated the effect of a serine protease inhibitor, N-alpha-tosyl-l-lysine chloromethyl ketone (TLCK), on hepatic allograft survival in rats. Methods. Orthotopic hepatic transplantation was performed in an ACI (RT1(a))-to-LEW (RT1(1)) rat combination. TLCK was administered continuously at a dose of 4.4 mg/kg/day using an osmotic subcutaneous infusion minipump.
TLCK prolonged hepatic allograft survival. Histologic staging of acute rejection based on Banff criteria in TLCK-treated hepatic allografts was significantly lower than in untreated allografts. TLCK significantly reduced serum concentrations of interferon (IFN)-gamma and tumor necrosis factor (TNF) alpha in allograft recipients. TNF-alpha mRNA levels in TLCK-treated allografts were significantly lower than in untreated allografts. TLCK also decreased perforin mRNA levels in hepatic allografts. Hepatic infiltrates eluted from TLCK-treated allografts showed significantly lower cell-mediated lympholytic activity against donor Con A blast cervical lymph node cells than those from untreated allografts. In vitro, TLCK suppressed interleukin-2 production and [(3)H]thymidine incorporation into an allogeneic mixed lymphocyte reaction.
TLCK suppressed acute allograft rejection, suggesting a novel immunosuppressive strategy for therapy of acute organ rejection.
丝氨酸蛋白酶抑制剂对细胞免疫和体液免疫反应具有显著的抑制作用。我们研究了一种丝氨酸蛋白酶抑制剂N-α-对甲苯磺酰-L-赖氨酸氯甲基酮（TLCK）对大鼠肝移植存活的影响。方法：采用ACI（RT1(a)）大鼠到LEW（RT1(1)）大鼠的组合进行原位肝移植。使用渗透性皮下输注微型泵以4.4mg/kg/天的剂量持续给予TLCK。
TLCK延长了肝移植的存活时间。根据Banff标准，TLCK处理的肝移植急性排斥反应的组织学分期显著低于未处理的移植。TLCK显著降低了移植受体血清中干扰素（IFN）-γ和肿瘤坏死因子（TNF）α的浓度。TLCK处理的移植中TNF-α mRNA水平显著低于未处理的移植。TLCK还降低了肝移植中穿孔素mRNA水平。从TLCK处理的移植中洗脱的肝浸润物对供体刀豆蛋白A刺激的颈淋巴结细胞的细胞介导淋巴细胞溶解活性显著低于未处理的移植。在体外，TLCK抑制白细胞介素-2的产生以及[³H]胸腺嘧啶核苷掺入同种异体混合淋巴细胞反应。
TLCK抑制急性移植排斥反应，提示一种治疗急性器官排斥反应的新型免疫抑制策略。
