Gene therapy using IL-27 ameliorates Sjögren's syndrome-like autoimmune exocrinopathy.
Gene therapy using IL-27 ameliorates Sjögren's syndrome-like autoimmune exocrinopathy.
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DOI：
10.1186/ar3925
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发表时间：
2012-07-24
影响因子：
4.9
通讯作者：
Nguyen CQ
中科院分区：
文献类型：
--
作者：
Lee BH;Carcamo WC;Chiorini JA;Peck AB;Nguyen CQ
Sjögren综合征（SjS）是一种系统性自身免疫性疾病，其特征是唾液和泪腺分泌减少，导致严重的口干和眼干。最近的研究表明，TH17细胞及其标志性细胞因子IL-17参与了导致破坏性炎症和自身免疫的潜在致病机制。在本研究中，我们检测了天然TH17活性抑制剂IL-27是否可以下调或逆转C57BL/6的SjS。NOD-Aec1Aec2小鼠，原发性sjs模型。将表达IL-27 （rAAV2-IL27）或LacZ （rAAV2-LacZ）的重组血清2型腺相关病毒（AAV2）载体注射到6或14周龄的C57BL/6中。NOD-Aec1Aec2老鼠。elisa检测外周血IL-27、IL-17和IL-10细胞因子水平的变化，流式细胞术检测细胞因子阳性的脾细胞。唾液腺的组织学评估、抗核自身抗体（ANA）染色和刺激唾液流速用于分析SjS疾病的严重程度。与接种后20周内注射rAAV2-LacZ或生理盐水的小鼠相比，在6或14周龄时全身静脉注射rAAV2-IL27的小鼠血清IL-27水平长期升高，同时IL-17水平降低。最重要的是，疾病谱显示rAAV2-IL27治疗对淋巴细胞病灶（LF）评分影响不大，但导致LF结构改变，ANAs滴度降低，染色模式改变，并且由唾液流速决定的临床疾病较轻。这些数据支持这样一个概念，即外源性提供IL-27可以诱导SjS发展的抑制作用，因此可能是调节自身免疫性疾病中TH17促炎活性的有效治疗药物，其中TH17系统已被证明在其发病机制中发挥重要作用。
Sjögren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of TH17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS. Recombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL-27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity. Mice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates. These data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating TH17 pro-inflammatory activity in autoimmune diseases where the TH17 system has been shown to play an important role in their pathogenesis.
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影响因子：
32.4
作者：
Hamano, S;Himeno, K;Yoshida, H
通讯作者：
Yoshida, H
影响因子：
5.4
作者：
Kaludov, N;Brown, KE;Chiorini, JA
通讯作者：
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影响因子：
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作者：
Grimm, D;Kern, A;Kleinschmidt, JA
通讯作者：
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影响因子：
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作者：
Hsu, Hui-Chen;Yang, PingAr;Mountz, John D.
通讯作者：
Mountz, John D.
DOI：
10.1016/s0022-5223(03)00082-5
发表时间：
2003-09-01
影响因子：
6
作者：
Chu, D;Sullivan, CC;Thistlethwaite, PA
通讯作者：
Thistlethwaite, PA