Targeting the class IA PI3K isoforms p110α/δ attenuates heart allograft rejection in mice by suppressing the CD4+ T lymphocyte response
Targeting the class IA PI3K isoforms p110α/δ attenuates heart allograft rejection in mice by suppressing the CD4+ T lymphocyte response
复制标题
靶向 IA 类 PI3K 亚型 p110α/δ 通过抑制 CD4 T 淋巴细胞反应来减轻小鼠心脏同种异体移植排斥
DOI：
--
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Jinping Liu
中科院分区：
文献类型：
--
作者：
Chuanlei Yang;Xing Chen;Zhanjie Wei;Jie Xiao;Weiqiang Chen;Yuqiang Shang;Jinping Liu
急性排斥反应是导致移植物失功的最重要因素，是器官移植患者面临的一个挑战。有相当多的证据表明，PI 3 K及其下游正和负调节因子的活性在调节效应CD 4 + T细胞的不同亚群的活化中起主要作用。因此，我们研究了A类PI 3 Ks是否参与了急性同种异体移植排斥反应的发生，我们发现同种异体移植组p110α蛋白表达水平在移植后第7天显著上调，而p110β和p110δ表达在移植后第5天和第7天显著上调。用PIK和IC治疗而不是TGX治疗显著延长了同种异体移植物的存活时间并改变了病理分级。IC治疗组脾脏中Th 1、Th 2、Th 17和Tfh细胞/单核细胞比例均下调。与此相反，IC治疗组脾脏中Treg细胞的百分比显著增加。IC组IL-17 A、IL-21和IFN-γ表达水平显著降低。此外，IC还显著降低P70 S6激酶β和4 E-BP 1蛋白的表达。总之，p110δ和p110α的小分子抑制剂抑制小鼠心脏移植物急性排斥反应。这些抑制剂可能通过影响AKT/mTOR通路中蛋白质的磷酸化和表达以调节受体中的CD 4 + T细胞亚群水平、减少促炎因子表达和增加抗炎细胞因子表达而在抗排斥中发挥作用。这些发现表明，一些小分子p110抑制剂可以作为新的目标，在急性移植排斥反应的治疗。
Acute rejection is the most important factor causing allograft loss, which remains a challenge for patients undergoing organ transplantation. There is considerable evidence indicating that the activity of PI3K and its downstream positive and negative regulators plays a major role in regulating the activation of different subsets of effector CD4+ T cells. Thus, we investigated whether class A PI3Ks are involved in the development of acute allograft rejection, we found that p110α protein expression levels in the allograft group were significantly up-regulated on day 7 post-transplantation, while p110β and p110δ expression was significantly increased on days 5 and 7 post-transplantation. Treatment with PIK and IC but not TGX significantly prolonged allograft survival and altered pathological grades. The percentages of Th1 and Th2, Th17 and Tfh cells/monocytes in the spleens from the IC treatment group were all down-regulated. In contrast, the percentage of Treg cells in the spleens from IC treatment group was remarkably increased. IL-17A and IL-21 and IFN-γ expression levels were significantly decreased in the IC group. Moreover, IC significantly reduced P70 S6 Kinase β and 4E-BP1 protein expression. In conclusion, small-molecule inhibitors of p110δ and p110α suppress acute heart allograft rejection in mice. These inhibitors may play a role in anti-rejection by impacting the phosphorylation and expression of proteins in the AKT/mTOR pathway to modulate CD4+ T cell subsets levels in recipients, reduce proinflammatory factor expression and increase anti-inflammatory cytokine expression. These findings indicate that some small-molecule inhibitors of p110 can serve as novel targets in acute allograft rejection treatment.