Lee C J, Yoshimura N, Shiho O, Kita M, Oka T
Second Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
Clin Exp Immunol. 1993 Mar;91(3):362-7. doi: 10.1111/j.1365-2249.1993.tb05910.x.
Considerable interest in the experimental and clinical use of MoAbs as potential therapeutic agents in allograft rejection has been generated by the recent reports of striking prolongation. In this study we investigated the efficacy of the local administration of MoAb OX-19 which is directed to the rat CD5 equivalent, through the renal artery using a rat kidney transplant model, in order to develop a potent method for modifying rejection while minimizing the systemic side effects. Untreated Lewis rats (LEW, RT-1(1)) rejected Brown-Norway rat (BN, RT-1n) kidney at 7.8 +/- 0.2 days (n = 10). Mean survival time (MST) of recipients treated with OX-19 (75 micrograms/kg per day) as single bolus injections via the dorsal penile vein for 7 days was 7.0 +/- 0.2 days (n = 5, NS). LEW hosts receiving OX-19 (75 micrograms/kg per day) continuously for 7 days via a femoral vein by using an osmotic minipump (IV-treated group) showed a slight prolongation of graft survival (MST = 8.8 +/- 0.9 days, n = 5), but this was not statistically significant. On the other hand, local continuous intrarenal arterial infusion of OX-19 (75 micrograms/kg per day) for 7 days (RA-treated group) significantly prolonged the graft survivals (MST = 16.8 +/- 1.3 days, n = 8, P < 0.01). Histological examination of MoAb-treated LEW hosts on day 6 post-grafting revealed that kidney grafts from RA-treated hosts showed a slight tubular necrosis, but reduced mononuclear cell infiltration, whereas kidney grafts from IV-treated hosts displayed a severe mononuclear cell infiltration around the artery with interstitial oedema. Moreover, the local intrarenal administration of OX-19, even when the dose is delayed until day 4 after renal grafting, has a therapeutic effect for on-going acute allograft rejection (MST = 11.4 +/- 0.8 days, n = 8) compared with administration of OX-19 intravenously from day 4 after grafting (MST = 7.6 +/- 0.2 days, n = 5, P < 0.01) or with no treatment (MST = 7.8 +/- 0.2 days, P < 0.01). The phenotype of graft infiltrating cells (GIC) was investigated on day 6 post-grafting. There was a significantly lower percentage of cells positive for OX-19, OX-8, OX-26 (transferrin receptor), and OX-39 (IL-2 receptor) in the RA group than in the IV group.(ABSTRACT TRUNCATED AT 400 WORDS)
近期关于显著延长移植物存活时间的报道引发了人们对单克隆抗体（MoAbs）作为同种异体移植排斥反应潜在治疗药物的实验和临床应用的浓厚兴趣。在本研究中，我们使用大鼠肾移植模型，通过肾动脉局部给予针对大鼠CD5等效物的单克隆抗体OX - 19，以开发一种在最小化全身副作用的同时有效改变排斥反应的方法。未处理的Lewis大鼠（LEW，RT - 1(1)）在7.8±0.2天（n = 10）时排斥Brown - Norway大鼠（BN，RT - 1n）的肾脏。通过阴茎背静脉以单次推注方式给予OX - 19（75微克/千克/天），持续7天的受体的平均存活时间（MST）为7.0±0.2天（n = 5，无统计学差异）。通过渗透微型泵经股静脉连续7天给予LEW宿主OX - 19（75微克/千克/天）（静脉注射治疗组），移植物存活时间略有延长（MST = 8.8±0.9天，n = 5），但这无统计学意义。另一方面，通过肾动脉局部连续输注OX - 19（75微克/千克/天），持续7天（肾动脉注射治疗组），显著延长了移植物存活时间（MST = 16.8±1.3天，n = 8，P < 0.01）。移植后第6天对接受单克隆抗体治疗的LEW宿主进行组织学检查发现，肾动脉注射治疗组宿主的肾移植显示有轻微的肾小管坏死，但单核细胞浸润减少，而静脉注射治疗组宿主的肾移植在动脉周围显示有严重的单核细胞浸润并伴有间质水肿。此外，即使将OX - 19的剂量延迟至肾移植后第4天进行肾内局部给药，与移植后第4天开始静脉注射OX - 19（MST = 7.6±0.2天，n = 5，P < 0.01）或不治疗（MST = 7.8±0.2天，P < 0.01）相比，对正在进行的急性同种异体移植排斥反应仍有治疗效果（MST = 11.4±0.8天，n = 8）。在移植后第6天研究移植物浸润细胞（GIC）的表型。肾动脉注射组中OX - 19、OX - 8、OX - 26（转铁蛋白受体）和OX - 39（IL - 2受体）阳性细胞的百分比显著低于静脉注射组。（摘要截短于400字）
