Restoring immunological tolerance in established experimental arthritis by combinatorial citrullinated peptides and immunomodulatory signals

Promoted tolerance is a coveted therapeutic approach for rheumatoid arthritis (RA), as current im-munosuppressive treatments are not disease-specific, primarily targeting the inflammatory response and exerting debilitating side effects. The cellular and antigenic complexity of RA challenges the design of nanoparticle-based tolerogenic strategies to selectively and comprehensively ameliorate joint destruction and restore immune tolerance in RA. Herein, we aimed at exploring the therapeutic effects and tolerogenic mechanism of a novel "tolerogenic polypeptide vaccine" (TPvax), which carried a multiepitope citrullinated peptide (Cit-ME) and rapamycin (Rapa), in established experimental arthritis. A low dose Rapa helped to drive the generation of anti-inflammatory cytokines and tolerogenic dendritic cells (DCs), thereby providing an immunosuppressive microenvironment for tolerance induction. We demonstrated that TPvax enabled the synergism between Cit-ME and Rapa, which led to the upregulation of regulatory T cells (Treg), pro-motion of IL-10 secretion and reduction of pro-inflammatory cytokines and antibody titers. Importantly, we provided evidence of epitope spreading to citrullinated antigens in collagen-induced arthritis (CIA) and demonstrated that co-delivery of Cit-ME and Rapa promoted immune tolerance even during an ongoing inflammatory event. This work would shed light to the development of tolerogenic therapeutics as novel immunotherapies for RA. (c) 2021 Elsevier Ltd. All rights reserved.