NEPHRUTIX:安慰剂与利妥昔单抗对照评估微小病变型肾病综合征的T细胞亚群变化

2021-09-15 从医路漫漫 MedSci原创

微小病变型肾病综合征(MCNS)是一种免疫介导的肾小球疾病,其特征是突发大量蛋白尿。MCNS在儿童和青年人中最常见。MCNS发病机制中涉及的免疫机制仍然不完全清楚。

 微小病变型肾病综合征(MCNS)是一种免疫介导的肾小球疾病,其特征是突发大量蛋白尿。MCNS在儿童和青年人中最常见。MCNS发病机制中涉及的免疫机制仍然不完全清楚。几十年前,有人认为MCNS是一种全身性T细胞功能障碍。这一假设得到了一些临床观察的支持,如抗原激发(感染或免疫)后迅速出现复发,过敏表现如接触性皮炎、鼻炎和哮喘,特别是MCNS儿童。在疾病的活跃期,一些T细胞亚群可能出现变化。

目的:我们进行了一项多中心、双盲、随机、安慰剂与利妥昔单抗对照试验,分析了23例使用高大剂量糖皮质激素/钙调神经磷酸酶抑制剂和/或霉酚酸酯治疗后频繁复发肾病综合征(FRNS)患者T细胞亚群的改变,患有FRNS的患者在缓解期进入试验,并被随机分组接受利妥昔单抗或安慰剂。在两组患者中,患者的血液样本在开始时进行分析,然后每月分析,直到使用6个月后。所有服用安慰剂显示复发的患者随后都接受了利妥昔单抗治疗。

结果:尽管免疫抑制药物显著减少,但利妥昔单抗组在内的所有患者都保持了缓解状态,只有一例患者(n=9/10)除外。另一方面,接受安慰剂治疗的所有患者在几周内(平均7.3周)均复发(n=13)。在利妥昔单抗治疗前,两组患者中不同T细胞亚群的数量非常相似,除了CD8+和不变的TCRVα24T细胞亚群,这两个T细胞亚群在安慰剂组患者中显著增加(分别为p=0.0414和p=0.0428)。尽管免疫抑制药物显著减少,包括利妥昔单抗组(n=10)在内的所有患者都保持缓解,只有一人除外。复发与CD4CD25HighFoxP3HighT调节细胞显著降低(p=0.0005)和IL-2表达显著降低(p=0.0032)有关,而CMIP丰度显著增加(p=0.03)有关。两组经利妥昔单抗治疗后均出现缓解,CD4+CD45RO+CXCR5+、不变自然杀伤T细胞(INKT)、CD4-CD8-(双阴性,DN)T细胞表达不变的Vα24链(DN-TCR Vα24)T细胞的频率均明显减少。

图1 安慰剂组和利妥昔单抗组中CD3+(A), CD4+(B)和CD8+(C)亚群的频率。图中显示了每个病人的百分比值。左图(A-C)表示纳入(P1)时安慰剂(P1- pl)与利妥昔单抗(P1- Rtx)之间的值。

数据显示为平均值±SEM。纳入CD3+和CD4+T-cell亚群时,未观察到显著(NS)差异(Mann-Whitney tests, p=0.055和p=0.2848)。安慰剂组CD8+T-cell亚群的频率明显

较低(Mann-Whitney tests, p=0.04)。中间和右边的面板显示了CD3+的变化(单因素方差分析,*p=0.01 18;随访期间CD4+(NS)和CD8+T-cell亚群

(单因素方差分析,***p<0.001;配对检验,* * p < 0.001)。缩写:P1(纳入时的分析,首次输注前(安慰剂或利妥昔单抗);BR(复发前);

Rel(复发)和M1-M5[利妥昔单抗后,分析包括利妥昔单抗治疗后(M1-M5)的1个月(M1)至5个月(M5)]。BR中的值对应于这段时间内每个患者所有样本的平均值。

同样,M1-M5期对应于每个患者在缓解期的所有样本的平均值。

图2 CD4+CD45RO+(A)、CD4+CD45RO+CD30+(B)、CD4+CD45RO+CXCR5+(C)和CD4+CD45RO+CD134+(D) T细胞亚群在安慰剂组和利妥昔单抗组患者中的出现频率。

数据显示平均值±SEM [B,RelvsP1 *p=0.013和M1-M5vsP1 *p=0.028;利妥昔单抗,M1-M5vsP1 *p=0.023,配对检验]。

图3 安慰剂组和利妥昔单抗组患者总INKT(A)、DN-INKT(B)、TCRα24(C)和DN-TCRα24(D)的频率。数据显示平均值±SEM (A安慰剂:P1vsM1-M5 *p=0.015,BRvsM1-M5 *p=0.020;

C安慰剂:P1-PLvsP1-Rtx *p<0.042, Mann-Whitney检验;D 安慰剂组:单因素方差分析,****p<0.0001;配对检验,M1-M5vsRel ****p<0.0001;利妥昔单抗:配对检验,P1vsM1-M5 **, p=0.0065)。

结论:MCNS涉及先天和获得性免疫应答紊乱,这种紊乱可以通过利妥昔单抗治疗来稳定。

原文出处

Boumediene A,  Vachin P,  Sendeyo K,NEPHRUTIX: A randomized, double-blind, placebo vs Rituximab-controlled trial assessing T-cell subset changes in Minimal Change Nephrotic Syndrome.J Autoimmun 2018 03;88

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