Chen Hao, Zheng Donghang, Ambadapadi Sriram, Davids Jennifer, Ryden Sally, Samy Hazem, Bartee Mee, Sobel Eric, Dai Erbin, Liu Liying, Macaulay Colin, Yachnis Anthony, Weyand Cornelia, Thoburn Robert, Lucas Alexandra
Department of Medicine, University of Florida, Gainesville, Florida, United States of America; Department of Molecular Genetics & Microbiology, University of Florida, Gainesville, Florida, United States of America.
Department of Medicine, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2015 Feb 6;10(2):e0115482. doi: 10.1371/journal.pone.0115482. eCollection 2015.
Giant cell arteritis (GCA) and Takayasu's disease are inflammatory vasculitic syndromes (IVS) causing sudden blindness and widespread arterial obstruction and aneurysm formation. Glucocorticoids and aspirin are mainstays of treatment, predominantly targeting T cells. Serp-1, a Myxomavirus-derived serpin, blocks macrophage and T cells in a wide range of animal models. Serp-1 also reduced markers of myocardial injury in a Phase IIa clinical trial for unstable coronary disease. In recent work, we detected improved survival and decreased arterial inflammation in a mouse Herpesvirus model of IVS. Here we examine Serp-1 treatment of human temporal artery (TA) biopsies from patients with suspected TA GCA arteritis after implant (TAI) into the aorta of immunodeficient SCID (severe combined immunodeficiency) mice. TAI positive for arteritis (GCApos) had significantly increased inflammation and plaque when compared to negative TAI (GCAneg). Serp-1 significantly reduced intimal inflammation and CD11b+ cell infiltrates in TAI, with reduced splenocyte Th1, Th17, and Treg. Splenocytes from mice with GCApos grafts had increased gene expression for interleukin-1 beta (IL-1β), IL-17, and CD25 and decreased Factor II. Serp-1 decreased IL-1β expression. In conclusion, GCApos TAI xenografts in mice provide a viable disease model and have increased intimal inflammation as expected and Serp-1 significantly reduces vascular inflammatory lesions with reduced IL-1β.
巨细胞动脉炎（GCA）和大动脉炎是炎症性血管炎综合征（IVS），可导致突然失明、广泛的动脉阻塞和动脉瘤形成。糖皮质激素和阿司匹林是主要治疗药物，主要针对T细胞。Serp-1是一种黏液瘤病毒衍生的丝氨酸蛋白酶抑制剂，在多种动物模型中可阻断巨噬细胞和T细胞。在一项针对不稳定型冠心病的IIa期临床试验中，Serp-1还降低了心肌损伤标志物。在最近的研究中，我们在IVS的小鼠疱疹病毒模型中检测到生存率提高和动脉炎症减轻。在此，我们研究了Serp-1对疑似TA GCA动脉炎患者的颞动脉（TA）活检组织植入免疫缺陷SCID（严重联合免疫缺陷）小鼠主动脉后的治疗效果。与阴性TAI（GCAneg）相比，动脉炎阳性的TAI（GCApos）炎症和斑块明显增加。Serp-1显著降低了TAI中的内膜炎症和CD11b+细胞浸润，同时脾细胞Th1、Th17和Treg减少。GCApos移植物小鼠的脾细胞白细胞介素-1β（IL-1β）、IL-17和CD25的基因表达增加，而凝血因子II减少。Serp-1降低了IL-1β的表达。总之，小鼠中的GCApos TAI异种移植物提供了一个可行的疾病模型，内膜炎症如预期增加，Serp-1显著减少血管炎性病变并降低IL-1β水平。
