Abstract：
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by abnormal activation of CD4+ T cells and an imbalance of T helper 17 (Th17) and regulatory T (Treg) cells. Tolerogenic therapy via administration of self-antigens is a promising strategy for RA treatment, but delivery of autoantigens alone may exacerbate disease conditions. Current studies indicated that codelivery of autoantigens with immunomodulators can lead to a more tolerogenic immune response. Here, we constructed an autoantigen type II collagen peptide (CII250-270)- and immunomodulator leflunomide (LEF)-coloaded phosphatidylserine liposome vaccine (CII250-270-LEF-PSL) for RA treatment via induction of tolerant dendritic cells (tolDC) for further activation of Treg cells. The in vivo results showed that CII250-270-LEF-PSL can effectively induce tolDC, regulate the balance of Th1/Th2 and Th17/Treg, and reduce the secretion of pro-inflammatory cytokines (IFN-γ, IL-1β, and IL-17A) and IgG antibodies to inhibit synovial inflammation and bone erosion. Furthermore, our study also suggested that LEF regulated Th1 cell differentiation by inhibiting the activation of the JAK1/STAT1 signaling pathway, further alleviating RA. Overall, this work proved that the combination of autoantigenic peptides and immunomodulators was a promising modality for RA treatment by reestablishing antigen-specific immune tolerance, which also inspired additional insights into the development of combination therapies for the tolerability of RA.
摘要：
类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特征是CD4T细胞的异常激活以及T辅助细胞17（Th17）和调节性T（Treg）细胞的失衡。通过给予自身抗原进行的耐受性治疗是RA治疗的一种有希望的策略，但是单独递送自身抗原可能会加剧疾病状况。目前的研究表明，自身抗原与免疫调节剂的共同递送可以导致更具耐受性的免疫应答。这里,我们构建了自身抗原II型胶原肽(CII250-270)-和免疫调节剂来氟米特(LEF)-负载磷脂酰丝氨酸脂质体疫苗(CII250-270-LEF-PSL),用于通过诱导耐受树突状细胞(tolDC)进一步激活Treg细胞治疗RA.体内实验结果表明,CII250-270-LEF-PSL能有效诱导tolDC,调节Th1/Th2和Th17/Treg的平衡，并减少促炎细胞因子的分泌(IFN-γ，IL-1β,和IL-17A）和IgG抗体，以抑制滑膜炎症和骨侵蚀。此外，我们的研究还表明，LEF通过抑制JAK1/STAT1信号通路的激活来调节Th1细胞的分化，进一步缓解RA。总的来说,这项工作证明，通过重建抗原特异性免疫耐受，自体抗原肽和免疫调节剂的组合是RA治疗的一种有前途的方式。这也激发了对RA耐受性联合疗法发展的更多见解。
