Autoantigenic Peptide and Immunomodulator Codelivery System for Rheumatoid Arthritis Treatment by Reestablishing Immune Tolerance

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 (CII_250–270)- and immunomodulator leflunomide (LEF)-coloaded phosphatidylserine liposome vaccine (CII_250–270-LEF-PSL) for RA treatment via induction of tolerant dendritic cells (tolDC) for further activation of Treg cells. The in vivo results showed that CII_250–270-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.