Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
PLoS One. 2020 Apr 16;15(4):e0227734. doi: 10.1371/journal.pone.0227734. eCollection 2020.
Both conventional and regulatory CD4+ T-cells rely on costimulatory signals mediated by cell surface receptors including CD28 for full activation. We showed previously that stimulation of CD4+ Foxp3+ regulatory T-cells by superagonistic anti-CD28 monoclonal antibodies (mAb) improves myocardial healing after experimental myocardial infarction (MI). However, the effect of ligand binding blocking anti-CD28 monoclonal antibodies has not yet been tested in this context. We hypothesize that ligand blocking anti-CD28 mAb treatment might favorably impact on healing after MI by limiting the activation of conventional CD4+ T-cells. Therefore, we studied the therapeutic effect of the recently characterized mAb E18 which blocks ligand binding to CD28 in a mouse permanent coronary ligation model. E18 or an irrelevant control mAb was applied once on day two after myocardial infarction to wildtype mice. Echocardiography was performed on day 7 after MI. E18 treatment improved the survival and reduced the incidence of left ventricular ruptures after experimental myocardial infarction. Accordingly, although we found no difference in infarct size, there was significantly less left ventricular dilation after E18 treatment in surviving animals as determined by echocardiography at day 7 after MI. In sham operated control mice neither antibody had an impact on body weight, survival, and echocardiographic parameters. Mechanistically, compared to control immunoglobulin, E18 treatment reduced the number of CD4+ T-cells and monocytes/macrophages within the infarct and periinfarct zone on day 5. This was accompanied by an upregulation of arginase which is a marker for alternatively differentiated macrophages. The data indicate that CD28-dependent costimulation of CD4+ T-cells impairs myocardial healing and anti-CD28 antibody treatment constitutes a potentially clinically translatable approach to improve the outcome early after MI.
传统和调节性 CD4+ T 细胞均依赖于细胞表面受体（包括 CD28）介导的共刺激信号以实现完全激活。我们之前曾表明，通过超激动型抗 CD28 单克隆抗体（mAb）刺激 CD4+Foxp3+调节性 T 细胞可改善实验性心肌梗死（MI）后的心肌愈合。但是，尚未在这种情况下测试配体结合阻断抗 CD28 单克隆抗体的效果。我们假设，配体阻断抗 CD28 mAb 治疗可能通过限制常规 CD4+ T 细胞的激活，对 MI 后愈合产生有利影响。因此，我们在小鼠永久性冠状动脉结扎模型中研究了最近表征的 mAb E18 的治疗效果，该 mAb 可阻断 CD28 与配体的结合。在 MI 后两天，将 E18 或无关对照 mAb 单次应用于野生型小鼠。MI 后 7 天进行超声心动图检查。E18 治疗可改善实验性心肌梗死后的存活率并降低左心室破裂的发生率。因此，尽管我们发现梗塞面积没有差异，但在 MI 后 7 天通过超声心动图检查，E18 治疗的存活动物的左心室扩张明显较小。在假手术对照小鼠中，两种抗体均未对体重、存活率和超声心动图参数产生影响。在机制上，与对照免疫球蛋白相比，E18 治疗可减少梗塞和梗塞周围区域内 CD4+T 细胞和单核细胞/巨噬细胞的数量，MI 后第 5 天。这伴随着精氨酸酶的上调，精氨酸酶是另一种分化的巨噬细胞的标志物。数据表明，CD28 依赖性共刺激 CD4+T 细胞会损害心肌愈合，而抗 CD28 抗体治疗可能是改善 MI 后早期预后的一种具有潜在临床转化价值的方法。
