Crescioli Clara, Squecco Roberta, Cosmi Lorenzo, Sottili Mariangela, Gelmini Stefania, Borgogni Elisa, Sarchielli Erica, Scolletta Sabino, Francini Fabio, Annunziato Francesco, Vannelli Gabriella Barbara, Serio Mario
Center for Research Transfer and High Education DENOthe, University of Florence, Florence, Italy.
Exp Cell Res. 2008 Apr 1;314(6):1337-50. doi: 10.1016/j.yexcr.2007.12.016. Epub 2008 Jan 4.
CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFNgamma and TNFalphaalpha; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNFalpha-induced up-regulation of IFNgammaR. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFNgamma-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.
CXCL10-CXCR3轴在心脏移植排斥反应中起关键作用，因此在不引起全身免疫抑制的情况下靶向CXCL10可能在同种异体移植中具有治疗意义。由于驻留细胞在心脏排斥反应中的作用仍不清楚，我们旨在建立可靠的人类心肌细胞培养体系，以研究同种异体移植排斥反应中Th1细胞因子介导的反应。我们使用从合法堕胎后获得的胎儿心脏中分离出的人类胎儿心肌细胞（Hfcm）。Hfcm表达特定的心脏谱系标志物、特定的心脏结构蛋白、典型的心脏电流并产生心室动作电位。因此，Hfcm代表了一种用于同种异体移植排斥反应研究的可靠体外工具，因为它们类似于成熟细胞的特征。Hfcm在受到IFNγ和TNFα刺激时分泌CXCL10；细胞因子组合可放大这种效应。细胞因子协同作用与TNFα诱导的IFNγR显著上调有关。还评估了Hfcm对一些目前使用的免疫抑制药物与罗格列酮（一种过氧化物酶体增殖物激活受体γ激动剂和Th1介导反应抑制剂）相比的反应。只有霉酚酸和罗格列酮使Hfcm分泌的CXCL10减少了一半。鉴于IFNγ诱导的趋化因子在Th1介导的同种异体移植排斥反应中的关键作用，这些初步结果表明免疫抑制剂和罗格列酮的联合作用可能对接受心脏移植的患者有潜在益处。
