Several studies reported the benefits of switching from anticalcineurins to mTOR inhibitors to avoid cancer occurrence after organ transplantation. The purpose of our study was to determine in vivo biological markers to explain these benefits. Cellular changes related to cellular senescence and DNA damage were analyzed in peripheral blood lymphocytes. Thirty-five kidney transplanted patients receiving anticalcineurins were investigated: 17 patients were proposed to switch to rapamycin and 18 patients with similar age and transplantation duration, continued anticalcineurins. Rapamycin effects were studied one year after the switch. Thirteen healthy volunteers and 18 hemodialyzed patients were evaluated as control. Compared with the healthy group, hemodialyzed and transplanted patients exhibited a significant decrease in telomere length, an increase in p16(INK4A) mRNA expression and in lymphocytes with 53BP1 foci. A destabilization of the shelterin complexes was suggested by a significant TIN2 mRNA decrease in transplanted patients compared with controls and a significant increase in TRF1, TRF2 and POT1 expression in switch-proposed patients compared with the non-switched subgroup. Rapamycin treatment resulted in a significant decrease in DNA damage and a slight TIN2 increase. In vitro experiments strengthened in vivo results showing that rapamycin but not FK506 induced a significant DNA damage decrease and TIN2 expression increase compared with controls. The roles of rapamycin in the decrease in DNA damage in vivo and the rescue of shelterin gene expression are demonstrated for the first time. These data provide new insights into understanding of how rapamycin may overcome genomic injuries.

中文翻译：

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雷帕霉素可保护淋巴细胞免受体内DNA损伤的积累。

几项研究报道了从抗神经尿素转换为mTOR抑制剂可避免器官移植后发生癌症的好处。我们研究的目的是确定体内生物学标志物以解释这些益处。在外周血淋巴细胞中分析了与细胞衰老和DNA损伤有关的细胞变化。对35名接受抗神经尿素的肾脏移植患者进行了研究：建议改用雷帕霉素治疗17例患者，年龄和移植时间相似的18例患者，继续抗神经酰胺治疗。转用一年后研究了雷帕霉素的作用。13名健康志愿者和18名血液透析患者被评估为对照组。与健康组相比，血液透析和移植患者的端粒长度明显减少，pBP（INK4A）mRNA表达的增加以及具有53BP1病灶的淋巴细胞的表达增加。与对照组相比，移植患者的TIN2 mRNA显着降低，而转换患者建议的TRF1，TRF2和POT1表达显着增加，这提示了避雷肽复合物的失稳。雷帕霉素治疗导致DNA损伤显着减少，而TIN2则略有增加。体外实验加强了体内结果，表明雷帕霉素而非FK506诱导的DNA损伤明显减少，而TIN2表达增加。雷帕霉素在体内DNA损伤减少和rehaventin基因表达的挽救中的作用首次得到证实。