尘螨基因树突状细胞疫苗在变应性鼻炎中促进IL-10+调节性B细胞介导免疫耐受的机制研究

It is well known that the immune regulation mechanism of allergic rhinitis (AR) is complex. There was strong evidence that the defect of immune tolerance mediated by regulatory B cells (Bregs) played an important role in the pathogenesis of AR. IL-10+Breg, which mainly produces IL-10, could inhibit the inflammatory response through JAK/STAT signaling pathway. Immune therapy could promote the immune tolerance mediated by Bregs. Immune therapy used in AR has a low effiency of immune reaction and limited curative effect as a result of few dendric cells (DCs) in immune reaction microenvironment. Therefore, it is urgent to improve the efficiency of immune therapy with the help of genetically modified DC. Our previous study found that the dust mite allergen Derp1 gene modified DC vaccine could improve the immune tolerance and increase the expression of IL-10 in AR mice, suggesting that IL-10+Breg mediated immune tolerance may be the latent immunotherapy mechanism. In this study，we will explore Breg-mediated immune tolerance induced by clinical immunotherapy in AR patients, and study DC vaccine to enhance Breg-mediated IL-10/JAK/STAT immune tolerance pathway in vitro and animal experiment. In addition, it can provide a new idea for exploring new immunoregulation mechnism and therapy of AR.

变应性鼻炎(allergic rhinitis,AR)的免疫机制复杂，现认为调节性B细胞(regulatory B cells,Bregs)介导的免疫耐受机制缺陷是AR重要发病机制，其中IL-10+Breg的作用是通过IL-10/JAK/STAT信号通路抑制炎性反应，免疫治疗可以促进Breg介导的免疫耐受。AR目前的免疫治疗由于微环境免疫反应效率低，治疗效果受到限制，而利用基因修饰树突状细胞(Dendric cell,DC)强化免疫是希望所在。我们的前期研究发现尘螨变应原基因修饰DC制备DC疫苗能够促进IL-10的表达，有效改善AR小鼠的免疫耐受，提示IL-10+Breg介导的免疫耐受可能是其潜在机制。本课题拟分析AR患者临床免疫治疗诱导Breg介导免疫耐受的机制，并分别体外及动物实验研究DC疫苗强化Breg介导的IL-10/JAK/STAT免疫耐受途径,深入探究AR免疫调控及治疗新机制。

变应性鼻炎(allergic rhinitis,AR)的发病机制复杂，研究发现调节性B细胞(regulatory B cell,Breg)介导的免疫耐受机制缺陷是AR重要发病机制。免疫治疗可以促进Breg介导的免疫耐受。AR目前的免疫治疗周期长且起效慢，存在一定的局限性，而利用尘螨变应原（Derp1）基因修饰树突状细胞(Dendric cell,DC)强化免疫有望提高免疫治疗效率。本课题通过AR患者临床免疫治疗诱导Breg介导免疫耐受的机制，并分别通过体外及动物实验研究DC疫苗强化Breg介导的IL-10/JAK/STAT免疫耐受途径，深入探究AR免疫调控及治疗新机制。研究结果如下：(1)特异性免疫治疗(specific immunotherapy, SIT)6个月后，AR患者鼻部症状显著改善，外周血Breg、Treg比例显著升高且呈正相关，血清IL-10、TGF-β升高，Th1/Th2平衡恢复；(2)Derp1慢病毒表达载体转染树突状细胞成功制备的Derp1-DC疫苗，可以在体外诱导B细胞向Breg分化，且Breg细胞对Th细胞的抑制作用主要依赖IL-10。(3)Derp1-DC腹腔注射治疗可以显著改善AR小鼠鼻部症状和过敏性炎症反应，同时通过诱导小鼠体内Breg细胞增值分化，强化Breg介导的IL-10/STAT3免疫耐受途径。以上结果表明：特异性免疫治疗可以通过升高AR患者体内Breg数量及其分泌的细胞因子水平参与形成免疫耐受；Derp1-DC疫苗免疫治疗可以诱导Breg细胞增值分化，增强Breg介导的IL-10/STAT3途径诱导免疫耐受。本课题首次通过尘螨变应原基因Derp1修饰DC的方式研究AR的免疫治疗，是对目前AR免疫治疗的创新性探索。本研究探讨了Breg在免疫治疗中诱导免疫耐受的机制以及相关的信号通路，为AR免疫治疗的机制研究奠定了良好的基础，也为AR免疫治疗提供了新的靶点和方向具有良好的临床应用前景。