CD4+LAP+ Treg 改善心肌梗死后不良心室重塑的作用及机制研究

Ventricular remodeling is the basic pathophysiological mechanism of heart failure after acute myocardial infarction (AMI). Increasing evidences suggest that AMI-induced inflammatory response is closely related to ventricular remodeling. CD4+LAP+ regulatory T cell (Tregs) is a newly identified subset of Tregs, which has been proved to inhibit immune response in many diseases. Our previous study showed CD4+LAP+ Tregs was reduced significantly and its function was impaired in AMI patients. Furthermore, adoptive transferred of CD4+LAP+Tregs significantly attenuated ventricular remodeling after AMI. However, the mechanism is unclear. We speculate that CD4+LAP+ Tregs can regulate immune response and ventricular remodeling after AMI. To confirm this hypothesis, we plan to 1 inject anti-LAP antibody and adoptively transfer CD4+LAP+ Tregs to AMI mice and observe the inflammatory response and ventricular remodeling post MI; 2 coculture CD4+LAP+ Tregs with cardiomyoctes to explore the further mechanism. This study aims to clarify the protective role and mechanism of CD4+LAP+ Tregs in ventricular remodeling after MI and provide a new theoretical and experimental basis for treating ventricular remodeling.

急性心肌梗死(AMI) 后心力衰竭发生发展的基本病理生理机制是心室重塑，越来越多证据表明AMI诱导的炎症反应与心室重塑密切相关。CD4+ LAP+ T 细胞是新发现的一类调节性T细胞，在多种疾病模型中发挥免疫抑制作用。我们前期研究显示，AMI患者外周血中CD4+LAP+ T细胞数目减少和功能受损。过继转输CD4+LAP+ T细胞可减缓MI后心室重塑进程。然其机制尚不清楚。我们推测，CD4+LAP+ T细胞可调控免疫炎症反应及MI后心室重塑进程。为证实本假说,拟：1，构建小鼠MI模型，注射抗LAP抗体和过继转输CD4+LAP+ T细胞两种方式，观察小鼠体内炎症反应及心室重塑变化；2，将CD4+LAP+ T细胞与心肌细胞共培养，探讨其作用机制。本研究可阐明CD4+LAP+ T细胞在MI后心室重塑中的作用，明确CD4+LAP+ T细胞抗心室重塑的机制，为防治MI后心室重塑提供新的理论和实验依据。

急性心肌梗死（AMI）具有高发病率、致死率、致残率的特点，严重威胁着人类的健康，AMI发病后数小时内发生心室重构，贯穿慢性心功能不的全程，是慢性心衰发展的关键。以往实验表明CD4+CD25+FOXP3+Treg调控AMI后的炎症从而减轻心室重塑，CD4+LAP+ Treg细胞是不同于经典CD4+CD25+FOXP3+Treg的一种调节性T细胞。我们的前期实验表明CD4+LAP+ Treg细胞在AMI患者外周血中比例下调，功能受损，然而CD4+LAP+ Treg细胞在心肌梗死后心室重塑中的作用仍未完全明确。本研究发现，建过继转输体外培养的CD4+LAP+ Treg细胞可以明显减轻AMI模型小鼠的心室重塑过程，表现为炎症反应被抑制，心功能得到改善,心室重塑减轻。抗体中和LAP可以下调AMI模型体内的CD4+LAP+ Treg细胞，并且发现心室重塑程度加重；将CD4+LAP+ Treg细胞与效应性T细胞共培养，发现心梗后CD4+LAP+ Treg细胞抑制效应T细胞的增殖功能减低；将CD4+LAP+ Treg细胞与心肌细胞共培养，发现心梗模型中的CD4+LAP+ Treg细胞抑制心肌细胞凋亡的功能减低。