R848对系统性红斑狼疮的免疫治疗作用与机制研究

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by auto-activated lymphocytes and large amount of autoantibodies. It affects mainly young women and has high possibility of mobidity and mortality. The treatment has remained largely symptomatic using non-specific conventional therapies which include nonsteroidal anti-inflammatory drugs, glucocorticoids, hydroxychloroquine and immunosuppressants. In addition to their modest therapeutic effect, these drugs have severe side effects. According to the abnormal dendritic cells and high levels of pro-inflammatory cytokines, such as IFN-α, IL-6, etc. we suggested that immune-regulatory method may balance the immune conditions of SLE. R848 is a TLR 7/8 agonist, it could induce immune responses through activating TLR 7/8. However, repeat injection of lower doses of R848 could induce TLR tolerance, a phenomenon discovered recently. We found also that R848 could induce normal mice tolerant to re-challenge of R848. Dendritic cells and B lymphocytes which express TLR7 could be suppressed and therefore the productions of IFN-α, IL-6, etc. were reduced. We hence proposed that R848 has the immune-therapeutic potential for SLE. In order to study whether R848 could ameliorate SLE and the underline mechanism, we will investigate the role of R848 on SLE mouse model, MRL/lpr mice, with in vitro and in vivo experiments. The results will discover the possible therapeutic role of R848 on SLE and such treatment strategy might be a new method to treat autoimmune diseases.

系统性红斑狼疮（SLE）是一种严重的系统性自身免疫性疾病，有很高的致残率和致死率。现有治疗方案以激素，免疫抑制剂及非甾体抗炎药为主，效果不理想，有严重毒副作用。R848是一种TOLL样受体（TLR）激动剂，但是低剂量多次应用，可诱导机体产生TLR耐受，减少炎症因子产生。我们的前期试验证实，小剂量R848于正常小鼠可诱导TLR耐受，减少IFN-α，白细胞介素6（IL-6）等炎症因子的产生。根据SLE的免疫学特征，即SLE患者体内存在异常的树突状细胞，I型干扰素及IL-6等炎症因子，我们提出假说：R848对SLE可能有免疫治疗作用。为验证此假说，我们拟采用R848对SLE小鼠模型, MRL/lpr小鼠，进行耐受诱导研究。利用体内外试验，探索R848对SLE小鼠模型的免疫治疗作用及机制。本研究有望阐明诱导TLR耐受治疗系统性红斑狼疮的机制，为自身免疫性疾病设计新的免疫治疗方案提供试验依据和参考。

R848是一种低分子量的合成的咪唑喹啉，具有有效的抗病毒活性，它可通过TLR7/TLR8 MyD88依赖性信号通路活化免疫细胞。但是也有研究发现，少量多次使用，R848可以诱导免疫耐受，从而有效抑制炎症反应。本研究通过少量多次的R848可体外成功诱导树突状细胞（dendritic cells, DC）耐受，下调白细胞介素6、12以及干扰素的产生。课题组前期研究发现，体外致耐受树突状细胞移植可有效缓解，甚至逆转类风湿性关节炎，因此，本研究采用多次R848注射系统性红斑狼疮（Systemic lupus erythematosus, SLE）小鼠模型，预期可通过诱导DC耐受而达到治疗SLE的目的。然后体内实验结果与体外实验结果出现了较大差异。治疗组与对照组的临床表现无统计学意义。通过机制研究，发现治疗组的树突状细胞被活化，产生大量的免疫细胞与免疫因子。反复多次注射R848未能成功诱导免疫耐受而促进SLE的缓解。然而，体内多次注射R848能诱导免疫细胞活化，对肿瘤动物模型的治疗是一个好的方式。因此，课题组采用R848与其他肿瘤治疗药物或免疫刺激物联合，通过诱导强免疫反应，发挥清除肿瘤，治疗肿瘤的作用。