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

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 (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.

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation

“…CD4 + T cells are considered crucial in the pathogenesis of RA. Upon antigen presentation by antigen-presenting cells (APCs) such as dendritic cells, CD4 + T cells are activated abnormally, showing an imbalance of Th1/Th2 and Th17/Treg, and migrate to the synovium, where they induce the activation and differentiation of macrophages and B cells through the secretion of cytokines or cell–cell contact [ 10 , 11 ]. CD4 + T cells in the joints of RA patients can activate macrophages through cell-to-cell contact, leading to the production of pro-inflammatory cytokines such as TNF, IL-1, and IL-6, which promote osteoclast differentiation, ultimately resulting in bone and cartilage destruction [ 12 ].…”