Calcineurin inhibitors (CNIs) are routinely used in immunosuppressive therapy and both Cyclosporine (CsA) and Tacrolimus (FK506) show similar efficacies to prevent rejection and death within the first year after organ transplantation. However, their use is limited by side effects such as kidney damage, hypertension, onset of diabetes and hyperlipidemia. It is a consensus that compared with CsA, FK506 causes less changes in blood pressures, serum lipids and renal function. Nevertheless, FK506 use is associated with a higher incidence of post-transplant diabetes mellitus (PTDM). FTY720 is a new compound that has shown a protective effect in animal models with respect to rejection in transplantation, ischemia-reperfusion injury, autoimmune diseases and tumor development. FTY720 acts by altering lymphocytes homing from blood to peripheral lymphoid organs. In mice, FTY720 administered in combination with CsA during 21 days has prolonged skin allograft survival without causing significant renal changes. In a model of CsA-induced chronic nephropathy in rats, FTY720 administration prevented renal injury suggesting benefit from using a combination of these drugs. In a canine kidney allograft model, FTY720 in combination with low doses of CsA or FK506 showed an addictive anti-rejection effect without causing critical adverse effects. We therefore, investigated whether 21 days of FTY720 administration in association with FK506 could prevent renal damage and development of diabetes in mice. Mice receiving FK506 alone or FTY720 + FK506 during 21 days showed changes in kidney function and structure besides an increase in blood glucose and lymphopenia. The FTY720 + FK506 combination requires further investigation with an aim toward understanding the mechanisms involved with respect to side effects.

译文

钙调神经磷酸酶抑制剂 (CNIs) 通常用于免疫抑制治疗,环孢素 (CsA) 和他克莫司 (FK506) 在器官移植后第一年内显示出相似的预防排斥反应和死亡的功效。但是,它们的使用受到诸如肾脏损害,高血压,糖尿病和高脂血症等副作用的限制。共识是,与CsA相比,FK506引起的血压,血脂和肾功能变化较小。然而,FK506的使用与移植后糖尿病 (PTDM) 的较高发生率相关。FTY720是一种新化合物,已在动物模型中显示出对移植排斥,缺血再灌注损伤,自身免疫性疾病和肿瘤发展的保护作用。FTY720通过改变从血液到周围淋巴器官的淋巴细胞归巢而起作用。在小鼠中,在21天内与CsA联合施用FTY720可延长皮肤同种异体移植的存活时间,而不会引起明显的肾脏变化。在CsA诱导的大鼠慢性肾病模型中,FTY720的给药可预防肾损伤,表明使用这些药物的组合可带来益处。在犬肾脏同种异体移植模型中,FTY720与低剂量的CsA或FK506组合显示出成瘾性抗排斥作用,而不会引起严重的不良反应。因此,我们研究了与FK506联合使用FTY720的21天是否可以预防小鼠的肾脏损害和糖尿病的发展。在21天内单独接受FK506或FTY720 FK506的小鼠显示出肾脏功能和结构的变化,以及血糖和淋巴细胞减少的增加。FTY720 + FK506组合需要进一步研究,目的是了解副作用相关的机制。

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