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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7
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Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

机译:通过诱导对Toll样受体7的耐受来预防自身免疫性疾病

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Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporespon-siveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phos-phatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.
机译:Toll样受体(TLR)的激活有助于自身免疫性疾病中慢性炎症的发生和维持,但是反复接触TLR激动剂会诱导对随后TLR刺激的反应低下。在这里,我们使用合成的TLR7激动剂9-苄基-8-羟基-2-(2-甲氧基乙氧基)腺嘌呤(SM360320,1V136)研究TLR7诱导的炎症反应减弱及其在自身免疫性疾病中的应用。在实验性变应性脑脊髓炎模型中,反复多次低剂量给予该TLR7激动剂会导致对TLR2,-7和-9激活剂反应低下或耐受,并限制了神经炎症的进程。低反应性不依赖于T或B淋巴细胞,但确实需要骨髓来源的细胞。此外,TLR7耐受性可减少被动抗体介导的关节炎模型中的炎症。 TLR7耐受性不会引起整体免疫抑制,因为对单核细胞增生性李斯特菌感染的敏感性没有改变。 TLR7耐受的机制涉及2种TLR信号抑制剂的上调:白介素1受体相关激酶(IRAK)M和含Src同源性2结构域的肌醇多磷酸磷酸酶(SHIP)-1。这些发现表明,诱导TLR7耐受性可能是缓解自身免疫性疾病炎症的新治疗方法。

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