The development of local immunosuppression in organ transplantation

在MoAbs的实验和临床用途中的可考虑利益，即在allograft拒绝中可能的治疗剂已被生成为最近的一份报告中的条纹延长。在这一研究中，我们研究了MoAb OX-19地方管理局的有效性，并将其定向到大鼠CD 5等价物，通过使用大鼠肾脏移植模型的一种可行的方法，在修改拒绝的同时，将系统侧面影响最小化。未处理的刘易斯大鼠（LEW，RT-1 <@D11 @>D1）拒绝的布朗-挪威大鼠（BN，RT-1 <@D1n @>D1）肾脏at 7·8（]SY.+-。[）0·2 Days （n=10）。用OX-19（75毫克/千克/天）治疗的受体的平均存活时间（MST），如单粒注射液通过阴道，7天为7.0（]SY.+-。[）0·2 Days （n=5， NS）。LEW主机接收OX-19（75微克/千克/天）连续7天通过使用运动微型水泵（IV治疗组）的女性阴道显示移植存活的缓慢延长（MST= 8.8（]SY.+-）。[0 - 9日] ... More n=5），但这不是统计意义上的。在其他手上，7天（RA治疗组）明确地描述移植幸存者的移植物（MST= 16.8（]SY.+-）的局部连续性动脉灌注OX-19（75微克/千克/天）。[）1·3 days， n=8， p<0·01。对Moab治疗的LEW主机每天6次后移植的历史性研究揭示了RA治疗的主机的肾脏移植显示了一个缓慢的管状坏死，但减少了单核细胞渗透，在IV治疗的主机中显示了一个严重的单核细胞渗透在一个带有国际仪器的多个单核细胞渗透。Moreover，OX-19的地方内部管理局，即使当放射性移植后4天的剂量延迟时，也有治疗效应（MST= 11.4（）SY.+-）。[）0·8天， n=8）与牛津-19管理局（MST=7·6（]SY.+-）比较。[）0·2 days， n=5， P<0·01） or with no treatment （MST=7·8（]SY.+-。[）0·2 Days， P<0·01。移植渗透细胞的表型（GIC）是在每天6后进行调查的。X-19、OX-8、OX-26（转运蛋白受体）和OX-39（IL-2受体）在RA组中的阳性率明显低于IV组。这一结果表明，通过放射性阵列对OX-19的地方管理是一种比系统i. v.注射更有效的治疗，并建议说，它可以提供一种局部免疫抑制，并减少临床移植受体中的发病率。Less（低）

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 CD5equivalent, 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<@D11@>D1) rejected Brown-Norway rat (BN,RT-1<@D1n@>D1) kidney at 7・8(]SY.+-。[)0・2 days (n=10). Mean survival time (MST) of recipients treated with OX-19 (75 mug/kg per day) as single bolus injections via the dorsal penile vein for 7 days was 7・0(]SY.+-。[)0・2 days (n=5, NS). LEW hosts receiving OX-19 (75 mug/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(]SY.+-。[)0・9 day … More s, n=5), but this was not statistically significant. On the other hand, local continuous intrarenal arterial infusion of OX-19 (75 mug/kg per day) for 7 days (RA-treated group) significantly prologed the graft survivals (MST=16・8(]SY.+-。[)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 displayd a severe mononuclear cell infiltration around the artery with interstitial oedema. Moreover, the local intrarenal administration of OX-19, even when the dose is delayd until day 4 after renal grafting, has a therapeutic effect for on-going acute allograft rejection (MST=11・4(]SY.+-。[)0・8 days, n=8) compared with administration of OX-19 intravenously from day 4 after grafting (MST=7・6(]SY.+-。[)0・2 days, n=5, P<0・01) or with no treatment (MST=7・8(]SY.+-。[)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. These results indicate that local administration of OX-19 via the renal artery is a more efficacious treatment than systemic i.v.injection, and suggests that it may provide a localized immunosuppression of allografts, with reduction of morbidity in clinical transplant recipients. Less