Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
Nephrol Dial Transplant. 2010 Jul;25(7):2159-67. doi: 10.1093/ndt/gfp775. Epub 2010 Jan 25.
BACKGROUND. The novel immunosuppressive agent AEB071 is currently being evaluated for its capability to prevent rejection after kidney transplantation as a potential adjunct to calcineurin inhibitor-based regimen. AEB071 is a selective protein kinase C inhibitor and has been shown to be well tolerated in humans. We here present extensive in vitro studies that contribute to the understanding of AEB071 effects on human lymphocyte, natural killer (NK) cell and dendritic cell (DC) action.
The impact of AEB071 on several T-cell activation and costimulatory markers was assessed. Furthermore, assays were performed to study the effect on T-cell proliferation and intracellular cytokine production. Additionally, the effect of AEB071 on DC maturation and their capacity to stimulate allogeneic T-cells was examined. Also, an evaluation of AEB071 effects on the lytic activity of human NK cells was performed.
We were able to show that T-cell proliferation and cytokine production rates are significantly reduced after AEB071 administration. Also, mitogen-induced T-cell activation characterized by expression levels of surface markers could be significantly inhibited. In contrast, the T-cell stimulatory capacity of AEB071-treated mature monocyte-derived DC (Mo-DC) is not reduced, and AEB071 administration does not prevent lipopolysaccharide (LPS)-induced Mo-DC maturation. It could be demonstrated that AEB071 significantly inhibited the cytotoxic activity of NK cells.
The promising immunosuppressive agent AEB071 has a strong impact on T-cell activation, proliferation and cytokine production as well as NK cell activity, but not DC maturation in vitro, and therefore, seems to function T-cell and NK cell specific via protein kinase C (PKC) inhibition.
背景。新型免疫抑制剂 AEB071 目前正在评估其作为钙调神经磷酸酶抑制剂方案的辅助药物预防肾移植后排斥反应的能力。AEB071 是一种选择性蛋白激酶 C 抑制剂，在人体中已被证明具有良好的耐受性。我们在此介绍了广泛的体外研究，有助于了解 AEB071 对人淋巴细胞、自然杀伤 (NK) 细胞和树突状细胞 (DC) 作用的影响。
评估了 AEB071 对几种 T 细胞活化和共刺激标志物的影响。此外，还进行了测定以研究对 T 细胞增殖和细胞内细胞因子产生的影响。此外，还研究了 AEB071 对 DC 成熟及其刺激同种异体 T 细胞能力的影响。还评估了 AEB071 对人 NK 细胞裂解活性的影响。
我们能够表明，AEB071 给药后 T 细胞增殖和细胞因子产生率显着降低。此外，可显著抑制有丝分裂原诱导的 T 细胞活化，其特征在于表面标志物的表达水平。相比之下，AEB071 处理的成熟单核细胞衍生的 DC（Mo-DC）的 T 细胞刺激能力没有降低，AEB071 给药不会阻止脂多糖 (LPS) 诱导的 Mo-DC 成熟。已证明 AEB071 可显着抑制 NK 细胞的细胞毒性活性。
有前途的免疫抑制剂 AEB071 对 T 细胞活化、增殖和细胞因子产生以及 NK 细胞活性具有强烈影响，但对体外 DC 成熟没有影响，因此似乎通过蛋白激酶 C（PKC）抑制起 T 细胞和 NK 细胞特异性作用。
