肠道菌群代谢产物联合CCR6抗体治疗系统性红斑狼疮的作用和机制研究

目前系统性红斑狼疮(SLE)的临床药物多为对症治疗并伴有严重副作用，60多年来针对SLE的药物研发收效甚微。申请人前期研究表明，膳食纤维及其肠道菌群代谢产物短链脂肪酸（SCFAs）可显著预防SLE和I型糖尿病等自身免疫性疾病。但针对体内已经存在大量致病性免疫细胞的SLE患者，SCFAs可能作用有限。据此申请人提出：首先利用合适抗体清除机体致病性免疫细胞重置免疫系统，然后联合SCFAs进行免疫干预，很可能根本性改善甚至治愈SLE。为了证明上述假说，申请人拟在hCCR6/BAFF-Tg自发SLE小鼠中，通过CCR6抗体清除导致SLE的Th17、Tfh和B细胞，使用SCFAs修饰的抗性淀粉诱导初始免疫细胞分化。研究两者恢复Th17/Treg平衡介导免疫耐受，治疗SLE的作用；进一步通过GPCRs和HDAC9等基因敲除小鼠揭示其分子机制。本项目的实施将为SLE的根本性治疗提供一个安全有效的新途径。

At present, the clinical drugs for systemic lupus erythematosus (SLE) are mostly symptomatic and accompanied by severe side effects. For more than 60 years, the development of drugs for SLE had few acquisition. The applicant's previous research showed that dietary fiber and its gut microbial metabolites, short-chain fatty acids (SCFAs), can significantly prevent autoimmune diseases such as SLE and type I diabetes. However, in SLE patients who already have a large number of pathogenic immune cells inside, SCFAs may have limited effect. Based on this, the applicant proposes that: firstly, using appropriate antibodies to clear the body's pathogenic immune cells to reset the immune system, then using SCFAs to conduct immune intervention, it is likely to radically improve or even cure SLE. In order to validate the above hypothesis, the applicant intends to use CCR6 depleting antibody in hCCR6/BAFF-Tg SLE mode mice to deplete Th17, Tfh and B cells that caused SLE, and then use SCFAs-modified resistant starch to lead the differentiation of naïve immune cells to recover the Th17/Treg balance and mediate the new immune tolerance. We will also further investigate and reveal the molecular mechanism of SCFAs effect for SLE through GPCRs and HDAC9 knockout mice. The implementation of this project will provide a safe and effective new way for the fundamental treatment of SLE.