Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice.
Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice.
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干扰素基因激动剂刺激剂可减轻 NOD 小鼠 I 型糖尿病的进展。
DOI：
10.1111/imm.13122
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发表时间：
2019
期刊：
影响因子：
6.4
通讯作者：
Mellor,AndrewL
中科院分区：
文献类型：
--
作者：
Lemos,Henrique;Mohamed,Eslam;Huang,Lei;Chandler,PhillipR;Ou,Rong;Pacholczyk,Rafal;Mellor,AndrewL
在多发性硬化和关节炎小鼠模型中，激活干扰素基因（STING）信号转导衔接子刺激因子的试剂可抑制实验诱导的自身免疫。在这项研究中，我们评估了STING激动剂作为抑制非肥胖糖尿病（NOD）雌性小鼠中自发性自身免疫性I型糖尿病（T1 D）发作的潜在试剂。当在T1 D发作之前施用时，用DNA纳米颗粒（DNP）（其在货物DNA被感测时激活STING）治疗延迟T1 D发作并降低T1 D发病率。DNP治疗提高了NOD小鼠脾脏、胰腺淋巴结和胰腺中吲哚胺2，3双加氧酶（IDO）的活性，该活性调节T细胞免疫。对DNP的治疗反应通过抑制IDO而部分逆转，并且DNP治疗与胰岛素治疗协同以进一步延迟T1 D发作并降低T1 D发病率。用环鸟苷腺苷二核苷酸（cGAMP）处理前驱糖尿病NOD小鼠以激活STING直接延迟T1 D发作并刺激干扰素-αβ（IFN-αβ），而用环二鸟苷酸（cdiGMP）处理在NOD小鼠中不延迟T1 D发作或诱导IFN-αβ。DNA序列分析显示，NOD小鼠具有STING多态性，这可能解释了对cGAMP和cdiGMP的不同反应。总之，STING激动剂减弱TlD进展，DNP增强对胰岛素疗法的治疗反应。
Reagents that activate the signaling adaptor stimulator of interferon genes (STING) suppress experimentally induced autoimmunity in murine models of multiple sclerosis and arthritis. In this study, we evaluated STING agonists as potential reagents to inhibit spontaneous autoimmune type I diabetes (T1D) onset in non‐obese diabetic (NOD) female mice. Treatments with DNA nanoparticles (DNPs), which activate STING when cargo DNA is sensed, delayed T1D onset and reduced T1D incidence when administered before T1D onset. DNP treatment elevated indoleamine 2,3 dioxygenase (IDO) activity, which regulates T‐cell immunity, in spleen, pancreatic lymph nodes and pancreas of NOD mice. Therapeutic responses to DNPs were partially reversed by inhibiting IDO and DNP treatment synergized with insulin therapy to further delay T1D onset and reduce T1D incidence. Treating pre‐diabetic NOD mice with cyclic guanyl‐adenyl dinucleotide (cGAMP) to activate STING directly delayed T1D onset and stimulated interferon‐αβ(IFN‐αβ), while treatment with cyclic diguanyl nucleotide (cdiGMP) did not delay T1D onset or induce IFN‐αβin NOD mice. DNA sequence analyses revealed that NOD mice possess a STING polymorphism that may explain differential responses to cGAMP and cdiGMP. In summary, STING agonists attenuate T1D progression and DNPs enhance therapeutic responses to insulin therapy.