Splenic Suppressor of Cytokine Signaling 3 Transgene Expression Affects T Cell Responses and Prevents Development of Collagen-Induced Arthritis
Splenic Suppressor of Cytokine Signaling 3 Transgene Expression Affects T Cell Responses and Prevents Development of Collagen-Induced Arthritis
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DOI：
10.1002/art.24072
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发表时间：
2008-12-01
影响因子：
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通讯作者：
van de Loo, Fons A. J.
中科院分区：
文献类型：
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作者：
Veenbergen, Sharon;Bennink, Miranda B.;van de Loo, Fons A. J.
Objective.细胞因子信号传导抑制因子（SOCS）家族的成员是细胞因子和生长因子应答的关键负性细胞内调节因子，包括调节自身免疫性疾病如类风湿性关节炎（RA）中的免疫应答的那些。本研究的目的是探讨通过静脉注射编码SOCS-3的腺病毒后增强脾抗原呈递细胞（APC）中SOCS-3的表达来调节T细胞免疫以治疗实验性关节炎。用11型胶原免疫DBA/1小鼠，并在胶原诱导的关节炎（CIA）临床发作前通过静脉注射给予腺病毒载体。通过使用Luminex多分析物技术测量细胞因子产生来分析脾细胞应答。流式细胞仪分析Th细胞群。编码SOCS-3的腺病毒的全身递送导致脾APC中转基因表达增强，这导致这些细胞产生白细胞介素-23（IL-23）、IL-6和肿瘤坏死因子α的减少，但显著增加IL-10的产生。免疫活化细胞分选分析显示SOCS-3处理后脾脏CD 4 + T细胞数量增加。然而，在SOCS-3转导的APC存在下，纯化的脾CD 3 + T细胞显示抗原特异性增殖减少，并且干扰素-γ（~ 43%）、IL-4（~ 41%）和IL-17（~ 70%）的产生显著减少。有趣的是，脾细胞反应的改变伴随着对CIA发展的保护作用，膝关节的组织学分析显示关节炎症和结缔组织破坏减少。这项研究表明，有效的预防CIA后静脉诱导过表达的SOCS-3，这可能是由产生的致耐受性APC，这对Th 1，Th 2，特别是Th 17细胞活性的抑制作用。
Objective. Members of the suppressor of cytokine signaling (SOCS) family are key negative intracellular regulators of cytokine and growth factor responses, including those that regulate immune responses in autoimmune disorders, such as rheumatoid arthritis (RA). The aim of this study was to investigate modulation of T cell immunity for the treatment of experimental arthritis, via enhanced expression of SOCS-3 in splenic antigen-presenting cells (APCs) obtained after intravenous injection of adenovirus encoding SOCS-3.Methods. DBA/1 mice were immunized with type 11 collagen, and adenovirus vectors were administered by intravenous injection before the clinical onset of collagen-induced arthritis (CIA). Splenic cellular responses were analyzed by measuring cytokine production, using Luminex multi-analyte technology. Th cell populations were analyzed by flow cytometry.Results. Systemic delivery of adenovirus encoding SOCS-3 resulted in enhanced transgene expression in splenic APCs, which led to decreased production of interleukin-23 (IL-23), IL-6, and tumor necrosis factor alpha, but significantly higher production of antiinflammatory IL-10, by these cells. Fluorescence-activated cell sorting analysis showed increased numbers of splenic CD4+ T cells after SOCS-3 treatment. In the presence of SOCS-3-transduced APCs, however, purified splenic CD3+ T cells showed reduced antigen-specific proliferation and a significant reduction in the production of interferon-gamma (-43%), IL-4 (-41%), and IL-17 (-70%). Interestingly, the altered splenic cellular responses were accompanied by a protective effect on CIA development, and histologic analysis of knee joints showed reduced joint inflammation and connective tissue destruction.Conclusion. This study demonstrates effective prevention of CIA after intravenously induced overexpression of SOCS-3; this is probably caused by the generation of tolerogenic APCs, which have an inhibitory effect on Th1, Th2, and especially, Th17 cell activity.