Inducible Adeno-Associated Virus-Mediated IL-2 Gene Therapy Prevents Autoimmune Diabetes
Inducible Adeno-Associated Virus-Mediated IL-2 Gene Therapy Prevents Autoimmune Diabetes
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DOI：
10.4049/jimmunol.1001422
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发表时间：
2011-03-15
影响因子：
4.4
通讯作者：
Tisch, Roland
中科院分区：
文献类型：
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作者：
Goudy, Kevin S.;Johnson, Mark C.;Tisch, Roland
IL-2和TGF-β 1在表达Foxp 3的CD 25（+）CD 4（+）T细胞（Foxp 3（+）Treg）的免疫生物学中起关键作用。这些细胞因子的施用提供了一种有吸引力的方法来操纵Foxp 3（+）Treg库并治疗T细胞介导的自身免疫，例如1型糖尿病。然而，细胞因子治疗的功效取决于应用模式，并且细胞因子如IL-2的有效多效性作用可能导致严重的副作用。在目前的研究中，我们使用了一种基于基因治疗的方法来评估重组腺相关病毒载体表达诱导型IL-2或TGF-β 1转基因抑制正在进行的β细胞自身免疫NOD小鼠的疗效。肌肉注射重组腺相关病毒接种10周龄NOD雌性小鼠，随后3周诱导IL-2足以预防糖尿病和阻断胰岛炎的进展。保护作用与外周以及引流胰腺淋巴结和胰岛中Foxp 3（+）Treg频率增加相关。IL-2诱导Foxp 3（+）Treg与IFN-γ表达T细胞浸润胰岛的比例发生变化。IL-2的诱导对T细胞和NK细胞的频率或活化状态没有全身性影响。尽管诱导的活化TGF-β 1的全身水平与IL-2相当，但TGF-β 1的诱导对Foxp 3（+）Treg库或β细胞自身免疫的进展没有影响。这些结果表明，诱导型IL-2基因治疗是操纵Foxp 3（+）Treg和抑制T细胞介导的自身免疫的有效且安全的方法，并且在所采用的条件下，IL-2比TGF-β 1更有效。免疫学杂志，2011，186：3779-3786。
IL-2 and TGF-beta 1 play key roles in the immunobiology of Foxp3-expressing CD25(+)CD4(+) T cells (Foxp3(+)Treg). Administration of these cytokines offers an appealing approach to manipulate the Foxp3(+)Treg pool and treat T cell-mediated autoimmunity such as type 1 diabetes. However, efficacy of cytokine treatment is dependent on the mode of application, and the potent pleiotropic effects of cytokines like IL-2 may lead to severe side effects. In the current study, we used a gene therapy-based approach to assess the efficacy of recombinant adeno-associated virus vectors expressing inducible IL-2 or TGF-beta 1 transgenes to suppress ongoing beta cell autoimmunity in NOD mice. Intramuscular vaccination of recombinant adeno-associated virus to 10-wk-old NOD female mice and a subsequent 3 wk induction of IL-2 was sufficient to prevent diabetes and block the progression of insulitis. Protection correlated with an increased frequency of Foxp3(+)Treg in the periphery as well as in the draining pancreatic lymph nodes and islets. IL-2 induced a shift in the ratio favoring Foxp3(+)Treg versus IFN-gamma-expressing T cells infiltrating the islets. Induction of IL-2 had no systemic effect on the frequency or activational status of T cells and NK cells. Induction of TGF-beta 1 had no effect on the Foxp3(+)Treg pool or the progression of beta cell autoimmunity despite induced systemic levels of activated TGF-beta 1 that were comparable to IL-2. These results demonstrate that inducible IL-2 gene therapy is an effective and safe approach to manipulate Foxp3(+)Treg and suppress T cell-mediated autoimmunity and that under the conditions employed, IL-2 is more potent than TGF-beta 1. The Journal of Immunology, 2011, 186: 3779-3786.