β-cell-specific IL-35 therapy suppresses ongoing autoimmune diabetes in NOD mice.
β-cell-specific IL-35 therapy suppresses ongoing autoimmune diabetes in NOD mice.
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DOI：
10.1002/eji.201646493
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发表时间：
2017-01
影响因子：
5.4
通讯作者：
Tisch R
中科院分区：
文献类型：
--
作者：
Manzoor F;Johnson MC;Li C;Samulski RJ;Wang B;Tisch R
IL-35 是最近发现的一种细胞因子，具有有效的免疫抑制特性。然而，IL-35 对致病性 T 效应 (Teff) 细胞和 Foxp3+ Treg 细胞的治疗潜力和作用尚不明确。我们测试了 IL-35 抑制 NOD 小鼠持续自身免疫的能力。为此，使用了腺相关病毒载体，其中IL-35转基因表达通过胰岛素启动子（AAV8mIP-IL35）选择性靶向β细胞。对处于 1 型糖尿病 (T1D) 临床前晚期阶段的 NOD 小鼠进行 AAV8mIP-IL35 疫苗接种可抑制 β 细胞自身免疫并预防糖尿病发作。 AAV8mIP-IL35 治疗后 4 周内，胰岛驻留的常规 CD4+ 和 CD8+ T 细胞以及 DC 的数量减少。胰岛 T 细胞库的减少与增殖抑制以及表达 IFN-γ 的 Teff 细胞频率降低相关。异位 IL-35 还减少了胰岛 Foxp3+ Treg 细胞的数量和增殖，并且保护作用独立于适应性胰岛免疫调节 T 细胞的诱导/扩增。这些发现表明，IL-35 介导的抑制足以阻断已建立的 β 细胞自身免疫，并支持使用 IL-35 治疗 T1D 和其他 T 细胞介导的自身免疫性疾病。
IL-35 is a recently identified cytokine exhibiting potent immunosuppressive properties. The therapeutic potential and effects of IL-35 on pathogenic T effector (Teff) cells and Foxp3+ Treg cells, however, are ill-defined. We tested the capacity of IL-35 to suppress ongoing autoimmunity in NOD mice. For this purpose, an adeno-associated virus vector in which IL-35 transgene expression is selectively targeted to β cells via an insulin promoter (AAV8mIP-IL35) was used. AAV8mIP-IL35 vaccination of NOD mice at a late preclinical stage of type 1 diabetes (T1D) suppressed β-cell autoimmunity and prevented diabetes onset. Numbers of islet-resident conventional CD4+ and CD8+ T cells, and DCs were reduced within 4 weeks of AAV8mIP-IL35 treatment. The diminished islet T-cell pool correlated with suppressed proliferation, and a decreased frequency of IFN-γ-expressing Teff cells. Ectopic IL-35 also reduced islet Foxp3+ Treg-cell numbers and proliferation, and protection was independent of induction/expansion of adaptive islet immunoregulatory T cells. These findings demonstrate that IL-35-mediated suppression is sufficiently robust to block established β-cell autoimmunity, and support the use of IL-35 to treat T1D and other T-cell-mediated autoimmune diseases.
影响因子：
5.4
作者：
Goudy, Kevin S.;Johnson, Mark C.;Garland, Alaina;Li, Chengwen;Samulski, Richard J.;Wang, Bo;Tisch, Roland
通讯作者：
Tisch, Roland