School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S30. doi: 10.1016/S0140-6736(15)60345-2.
Cardiovascular risk is increased in the anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). CD4+CD28- T cells are expanded in patients with AAV who are seropositive for cytomegalovirus (CMV), and are associated with increased mortality. CMV seropositivity in other conditions is associated with arterial stiffness, a marker of cardiovascular risk. We assessed whether CD4+CD28- T cells in CMV seropositive patients with AAV are associated with arterial stiffness and whether treatment with valaciclovir reduces this cell population.
In this open-label phase 2 trial, patients were randomised (1:1) by computer to valaciclovir (8 g daily) or no additional treatment for 6 months. Primary outcome was proportion of patients with CMV reactivation. Arterial stiffness (carotid to femoral pulse wave velocity [PWV]) was measured and peripheral blood CD4+CD28- T cells analysed by flow cytometry at baseline and 6 months. CD4+CD28- T-cell interferon γ (IFNγ) secretion was stimulated with CMV lysate. Data are presented as median (IQR). Between-group differences were tested by Mann-Whitney U test and correlations by Spearman's rank. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01633476.
Baseline data are presented from the first 28 patients enrolled, with 6 months' follow-up completed in five treatment and six control patients. More CD4+CD28- than CD4+CD28+ T cells expressed T-bet (83·5% [47·5-89·9] vs 12·9 [4·7-22·2], p<0·0001) and secreted IFNγ after stimulation (14·3% [8·4-26·0] vs 0·8 [0·2-1·3], p<0·0001). CX3CR1, a cell surface marker whose expression is associated with endothelial dysfunction, was only expressed on CD4+CD28- T cells. The proportion of CD4+CD28- T cells correlated with PWV (r=0·408, p=0·035). At 6 months, reduction in proportion of CD4+CD28- T cells was greater in the treatment than in the control group (-1·8% [-5·2 to -0·6] vs 0·5 [-0·8 to 2·5], p=0·044).
These preliminary results suggest that CD4+CD28- T cells in AAV are proinflammatory cells with high expression of the fractalkine receptor CX3CR1 that has been implicated in endothelial dysfunction. This cell population is associated with arterial stiffness, and its expansion is attenuated with valaciclovir treatment. This research has important implications, because cardiovascular disease is a major cause of mortality in AAV.
Wellcome Trust, Vasculitis UK.
抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）患者心血管风险增加。巨细胞病毒（CMV）血清阳性的 AAV 患者中存在 CD4+CD28-T 细胞扩增，与死亡率增加有关。其他疾病中的 CMV 血清阳性与动脉僵硬有关，这是心血管风险的一个标志物。我们评估了 AAV 中 CMV 血清阳性患者的 CD4+CD28-T 细胞是否与动脉僵硬有关，以及缬昔洛韦治疗是否可以减少这种细胞群。
在这项开放标签的 2 期临床试验中，患者通过计算机按 1:1 的比例随机分配至缬昔洛韦（每天 8 克）或无额外治疗的对照组，持续 6 个月。主要终点是 CMV 再激活的患者比例。基线和 6 个月时，通过颈动脉-股动脉脉搏波速度（PWV）测量动脉僵硬情况，并通过流式细胞术分析外周血 CD4+CD28-T 细胞。用 CMV 裂解物刺激 CD4+CD28-T 细胞干扰素γ（IFNγ）分泌。数据以中位数（IQR）表示。采用 Mann-Whitney U 检验比较组间差异，Spearman 秩相关分析相关性。分析采用意向治疗。该试验在 ClinicalTrials.gov 注册，编号为 NCT01633476。
本研究报告了前 28 名入组患者的基线数据，其中 5 名治疗组和 6 名对照组患者完成了 6 个月的随访。与 CD4+CD28+T 细胞相比，更多的 CD4+CD28-T 细胞表达 T 细胞因子盒蛋白 1（T-bet）（83.5%[47.5-89.9]vs 12.9%[4.7-22.2]，p<0.0001），并且在刺激后分泌更多的 IFNγ（14.3%[8.4-26.0]vs 0.8[0.2-1.3]，p<0.0001）。CX3CR1 是一种细胞表面标志物，其表达与内皮功能障碍有关，仅在 CD4+CD28-T 细胞上表达。CD4+CD28-T 细胞的比例与 PWV 相关（r=0.408，p=0.035）。6 个月时，治疗组 CD4+CD28-T 细胞比例的下降幅度大于对照组（-1.8%[-5.2 至-0.6]vs 0.5[-0.8 至 2.5]，p=0.044）。
这些初步结果表明，AAV 中的 CD4+CD28-T 细胞是具有高表达趋化因子受体 CX3CR1 的促炎细胞，该受体与内皮功能障碍有关。该细胞群与动脉僵硬有关，缬昔洛韦治疗可减轻其扩增。这项研究具有重要意义，因为心血管疾病是 AAV 患者死亡的主要原因。
英国惠康基金会，血管炎英国。
