直接作用抗病毒疗法恢复丙型肝炎病毒相关冷球蛋白血症血管炎患者的免疫耐受。
Direct-Acting Antiviral Therapy Restores Immune Tolerance to Patients With Hepatitis C Virus-Induced Cryoglobulinemia Vasculitis.
机构信息
Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (département hospitalo-unniversitaire i2B), Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, unité mixte de recherche 7211, Paris, France; INSERM, unité mixte de recherche_S 959, Paris, France; centre national de recherche et de santé, FRE3632, Paris, France; Département de Médecine Interne et Immunologie Clinique, Paris, France.
Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (département hospitalo-unniversitaire i2B), Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, unité mixte de recherche 7211, Paris, France; INSERM, unité mixte de recherche_S 959, Paris, France; centre national de recherche et de santé, FRE3632, Paris, France.
出版信息
Gastroenterology. 2017 Jun;152(8):2052-2062.e2. doi: 10.1053/j.gastro.2017.02.037. Epub 2017 Mar 6.
BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity.
METHODS
We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay.
RESULTS
Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively).
CONCLUSIONS
In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
背景与目的
无干扰素直接作用抗病毒（DAA）疗法可有效治疗丙型肝炎病毒诱导的冷球蛋白血症血管炎（HCV-CV）患者。我们分析了 HCV-CV 患者 DAA 治疗前后的血液样本，以确定这些药物的作用机制及其对细胞免疫的影响。
方法
我们对法国巴黎的 27 例连续 HCV-CV 患者（中位年龄 59 岁）进行了前瞻性研究，这些患者接受了 DAA 治疗（21 例患者接受索非布韦联合利巴韦林治疗 24 周，4 例患者接受索非布韦联合达拉他韦治疗 12 周，2 例患者接受索非布韦联合西米普韦治疗 12 周）。从这些患者 DAA 治疗前后、12 例健康供者和 12 例无 CV 的 HCV 感染个体采集血液样本。采用流式细胞术、细胞因子多重分析和酶联免疫吸附试验定量检测 HCV 载量、冷球蛋白和细胞因子。
结果
24 例（88.9%）患者在第 24 周时 CV 完全缓解，定义为所有受累器官改善且无复发。与健康供者和无 CV 的 HCV 感染个体相比，HCV-CV 患者在 DAA 治疗前，CD4+CD25hiFoxP3+调节性 T 细胞比例较低（P<0.01），但 IgM+CD21-/low 记忆 B 细胞比例较高（P<0.05）、CD4+IFNγ+细胞比例较高（P<0.01）、CD4+IL17A+细胞比例较高（P<0.01）和 CD4+CXCR5+白细胞介素 21+滤泡辅助性 T 细胞（Tfh）比例较高（P<0.01）。在 HCV-CV 患者中，IgM+CD21-/low 记忆 B 细胞数量与 T 调节细胞数量呈负相关（P=0.03），与 Tfh 细胞数量呈正相关（P=0.03），与血清冷球蛋白水平呈正相关（P=0.01）。DAA 治疗增加了患者的 T 调节细胞数量（治疗前 1.5%±0.18%，治疗后 2.1%±0.18%），降低了 IgM+CD21-/low 记忆 B 细胞比例（治疗前 35.7%±6.1%，治疗后 14.9%±3.8%），降低了 Tfh 细胞数量（治疗前 12%±1.3%，治疗后 8%±0.9%）。接受 DAA 治疗后，HCV-CV 患者 B 细胞上的 B 淋巴细胞刺激受体 3 和程序性细胞死亡蛋白 1 的表达水平升高（平均荧光强度，治疗前 37±2.4，治疗后 47±2.6，P<0.01；治疗前 29±7.3，治疗后 48±9.3，P<0.05）。
结论
在一项 HCV-CV 患者的前瞻性临床试验中，DAA 治疗恢复了外周 B 细胞和 T 细胞的稳态失调。
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