Department of Pathobiology, School of Public Healths, Tehran University of Medical Sciences, Tehran, Iran.
Chronic Kidney Disease Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Hum Immunol. 2019 Sep;80(9):739-747. doi: 10.1016/j.humimm.2018.12.010. Epub 2018 Dec 28.
Accumulating evidence suggests that regulatory T cells (Tregs) have a crucial role in immune tolerance and long-term graft survival. However, the influence of immunosuppressive drugs on the level of Tregs has not been fully understood. Therefore we prospectively compare the effect of two different calcineurin inhibitor (CNI)-based immunosuppression protocols on Tregs frequencies and expression of regulatory and effector T cell-related genes in renal transplant recipients.
The study included 24 renal transplant recipients who received induction therapy (Antithymocyte globulin) and were on triple immunosuppressive therapy so that one group was on Tacrolimus (Tac), mycophenolate moftile (MMF) and prednisolone (P) whereas another group was on Tac, Sirolimus (SRL) and P. The frequency of circulating Treg cells was analyzed by flow cytometry before and 4 months after transplantation. Also, the mRNA expression of FOXP3, T-bet, GATA3 and RORγt was examined by quantitative RT-PCR before and 4 months after transplantation.
Compared to baseline, the frequency of CD4 CD25 FOXP3 Treg cells was significantly increased in the all patients following transplantation. Patients who received Tac/MMF had significantly higher CD4 CD25 FOXP3 Treg cells compared to patients who received Tac/SRL. There was no a significant difference in the frequency of CD3CD8 CD28 Tregs between two different calcineurin inhibitor (CNI)-based immunosuppression protocols. FOXP3 mRNA levels in the patients who received Tac/MMF were increased 4 months after transplantation and the expression was significantly higher than patients who received Tac/SRL. On the other hand, T-bet and RORγt expression levels were significantly lower in the Tac/SRL group in comparison to Tac/MMF group. We did not observe any significant difference in GATA3 mRNA level between the two groups.
Our results suggest that although Tac/MMF-containing immunosuppressive regimen could significantly increase the frequency of CD4 CD25 FOXP3 Tregs, unlike to Tac/SRL-containing regimen, it could not significantly decrease the expression levels of RORγt and T-bet.
越来越多的证据表明调节性 T 细胞（Tregs）在免疫耐受和长期移植物存活中起着关键作用。然而，免疫抑制剂对 Tregs 水平的影响尚未完全阐明。因此，我们前瞻性比较了两种不同的钙调神经磷酸酶抑制剂（CNI）为基础的免疫抑制方案对肾移植受者 Tregs 频率以及调节性和效应性 T 细胞相关基因表达的影响。
本研究纳入了 24 例接受诱导治疗（抗胸腺细胞球蛋白）并接受三联免疫抑制治疗的肾移植受者，其中一组接受他克莫司（Tac）、霉酚酸酯（MMF）和泼尼松（P）治疗，另一组接受他克莫司、西罗莫司（SRL）和 P 治疗。在移植前和移植后 4 个月，通过流式细胞术分析循环 Treg 细胞的频率。此外，在移植前和移植后 4 个月，通过定量 RT-PCR 检测 FOXP3、T-bet、GATA3 和 RORγt 的 mRNA 表达。
与基线相比，所有患者在移植后 CD4 CD25 FOXP3 Treg 细胞的频率均显著增加。接受 Tac/MMF 治疗的患者与接受 Tac/SRL 治疗的患者相比，CD4 CD25 FOXP3 Treg 细胞明显更高。两种不同的钙调神经磷酸酶抑制剂（CNI）为基础的免疫抑制方案之间，CD3CD8 CD28 Tregs 的频率无显著差异。接受 Tac/MMF 治疗的患者，FOXP3 mRNA 水平在移植后 4 个月增加，表达水平明显高于接受 Tac/SRL 治疗的患者。另一方面，与 Tac/MMF 组相比，Tac/SRL 组的 T-bet 和 RORγt 表达水平明显降低。我们未观察到两组间 GATA3 mRNA 水平的显著差异。
我们的研究结果表明，虽然 Tac/MMF 为基础的免疫抑制方案可以显著增加 CD4 CD25 FOXP3 Tregs 的频率，但与 Tac/SRL 为基础的免疫抑制方案不同，它不能显著降低 RORγt 和 T-bet 的表达水平。
