Sottili M, Cosmi L, Borgogni E, Sarchielli E, Maggi L, Francalanci M, Vannelli G B, Ronconi E, Adorini L, Annunziato F, Romagnani P, Serio M, Crescioli C
Excellence Center for Research Transfer and High Education DENOthe, University of Florence, Italy.
Exp Cell Res. 2009 Jan 15;315(2):264-73. doi: 10.1016/j.yexcr.2008.10.025. Epub 2008 Nov 5.
Current immunosuppressive protocols have reduced rejection occurrence in heart transplantation; nevertheless, management of heart transplant recipients is accompanied by major adverse effects, due to drug doses close to toxic range. In allograft rejection, characterized by T-helper 1 (Th1) cell-mediated response, the CXCL10-CXCR3 axis plays a pivotal role in triggering a self-promoting inflammatory loop. Indeed, CXCL10 intragraft production, required for initiation and development of graft failure, supports organ infiltration by Th1 cells. Thus, targeting the CXCL10-CXCR3 axis while avoiding generalized immunosuppression, may be of therapeutic significance. Based on preclinical evidence for immunoregulatory properties of vitamin D receptor agonists, we propose that a less hypercalcemic vitamin D analogue, BXL-01-0029, might have the potential to contribute to rejection management. We investigated the effect of BXL-01-0029 on CXCL10 secretion induced by proinflammatory stimuli, both in human isolated cardiomyocytes (Hfcm) and purified CD4+ T cells. Mycophenolic acid (MPA), the active agent of mycophenolate mofetil, was used for comparison. BXL-01-0029 inhibited IFNgamma and TNFalpha-induced CXCL10 secretion by Hfcm more potently than MPA, impairing cytokine synergy and pathways. BXL-01-0029 reduced also CXCL10 protein secretion and gene expression by CD4+ T cells. Furthermore, BXL-01-0029 did not exert any toxic effect onto both cell types, suggesting its possible use as a dose-reducing agent for conventional immunosuppressive drugs in clinical transplantation.
目前的免疫抑制方案已降低了心脏移植中排斥反应的发生率；然而，由于药物剂量接近毒性范围，心脏移植受者的管理伴随着严重的不良反应。在以辅助性T细胞1（Th1）介导的反应为特征的同种异体移植排斥中，CXCL10-CXCR3轴在触发自我促进的炎症循环中起关键作用。事实上，移植内CXCL10的产生是移植失败起始和发展所必需的，它支持Th1细胞浸润器官。因此，在避免全身免疫抑制的同时靶向CXCL10-CXCR3轴可能具有治疗意义。基于维生素D受体激动剂免疫调节特性的临床前证据，我们提出一种低高钙血症的维生素D类似物BXL-01-0029可能有助于排斥反应的管理。我们研究了BXL-01-0029对促炎刺激诱导的CXCL10分泌的影响，该刺激在人分离的心肌细胞（Hfcm）和纯化的CD4+T细胞中均有发生。霉酚酸（MPA），霉酚酸酯的活性成分，用于比较。BXL-01-0029比MPA更有效地抑制IFNγ和TNFα诱导的Hfcm中CXCL10的分泌，损害细胞因子协同作用和信号通路。BXL-01-0029还降低了CD4+T细胞中CXCL10蛋白的分泌和基因表达。此外，BXL-01-0029对这两种细胞类型均未产生任何毒性作用，表明其可能用作临床移植中传统免疫抑制药物的剂量减少剂。
