Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion
Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion
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DOI：
10.1038/labinvest.2009.3
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发表时间：
2009-04-01
影响因子：
5
通讯作者：
Jimenez, Eva
中科院分区：
文献类型：
--
作者：
Arias-Diaz, Javier;Ildefonso, Jose A.;Jimenez, Eva
免疫抑制剂对缺血/再灌注（I/R）损伤的保护作用归因于其非特异性抗炎作用。然而，这些作用也可能取决于它们对T淋巴细胞的作用，T淋巴细胞越来越多地被认为是I/R的关键参与者。在此，我们研究了他克莫司和西罗莫司对I/R大鼠模型淋巴细胞亚群的影响。动物接受他克莫司、西罗莫司或溶媒治疗，然后进行60分钟的肝右叶缺血事件，随后切除剩余肝脏。2 h后，I/R大鼠死亡率、血浆乳酸脱氢酶（LDH）水平、肝细胞凋亡、肝组织学损伤和中性粒细胞、巨噬细胞、NK细胞和T淋巴细胞的实质浸润增加。两种免疫抑制剂均可拮抗大部分变化。他克莫司增加了I/R大鼠中周期细胞的比例，而西罗莫司则表现出相反的效果。免疫抑制剂可逆转I/R肝2 h后Th 1/Th 2比值的升高，并在24 h时增加CD 4（+）CD 25（+）Foxp 3（+）调节性T淋巴细胞的比例。他克莫司和西罗莫司的保护作用与促炎与抗炎T淋巴细胞比例的降低以及Treg比例的增加密切相关。这表明了一种新的机制来解释I/R后早期免疫抑制剂显示的已知有益作用。
The protective effects of immunosuppressants against ischemia/reperfusion (I/R) injury have been attributed to their non-specific anti-inflammatory effect. However, these effects may also depend on their effect on T lymphocytes, which are increasingly considered to be key players in I/R. Here, we studied the effects of tacrolimus and sirolimus on lymphocyte subpopulations in an I/R rat model. The animals were treated with tacrolimus, sirolimus or vehicle, before undergoing a 60-min ischemia event of the right hepatic lobe, followed by excision of the remaining liver. After 2 h, I/R rats showed increased mortality, plasma lactate dehydrogenase (LDH) levels, hepatocyte apoptosis, liver histological injury and parenchymal infiltration by neutrophils, macrophages, NK cells and T lymphocytes. Most of the changes were antagonized by both immunosuppressants. Tacrolimus augmented the proportion of cycling cells in I/R rats, whereas sirolimus showed the opposite effect. The increased Th1/Th2 ratio found in I/R livers after 2 h was reverted by immunosuppressants, which also amplified the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T lymphocytes at 24 h. The protective effects of both tacrolimus and sirolimus correlated well with a decreased ratio of proinflammatory to anti-inflammatory T lymphocytes, and with an increase in the Treg proportion. This suggests a new mechanism to explain the known beneficial effect shown by immunosuppressants early after I/R.