Dendritic cells and the promise of antigen-specific therapy in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease resulting from an autoimmune response to self-antigens, leading to inflammation of synovial tissue of joints and subsequent cartilage and bone erosion. Current disease-modifying anti-rheumatic drugs and biologic inhibitors of TNF, IL-6, T cells and B cells block inflammation nonspecifically, which may lead to adverse effects, including infection. They do not generally induce long-term drug-free remission or restoration of immune tolerance to self-antigens, and lifelong treatment is usual. The development of antigen-specific strategies in RA has so far been limited by insufficient knowledge of autoantigens, of the autoimmune pathogenesis of RA and of the mechanisms of immune tolerance in man. Effective tolerance-inducing antigen-specific immunotherapeutic strategies hold promise of greater specificity, of lower toxicity and of a longer-term solution for controlling or even preventing RA. This paper reviews current understanding of autoantigens and their relationship to immunopathogenesis of RA, and emerging therapeutics that aim to leverage normal tolerance mechanisms for implementation of antigen-specific therapy in RA.

Figure 1

Principles underlying the induction of antigen-specific regulation. (a) Mucosal tolerance. Rheumatoid arthritis (RA) self-antigen is delivered to the mucosal immune system by the oral or nasal route. If taken up and presented by the appropriate CD103⁺ dendritic cells (DCs), which reside in the transforming growth factor-beta (TGFβ)-rich gut lamina propria and draining lymph nodes, antigen-specific regulatory T cells (Tregs) can be induced in the presence of all-trans retinoic acid (ATRA). These Tregs should suppress RA self-antigen-specific immune responses in the joint. (b) Tolerising DC immunotherapy. DCs with tolerising capacity are generated from peripheral blood monocytes in vitro in the presence of inhibitory drugs to prevent DC activation after contact with Toll-like receptor ligands or cytokines. The DCs are then exposed to RA self-antigen and washed. The antigen-presenting DCs are injected and should induce antigen-specific Tregs in draining lymph nodes. These Tregs should suppress RA self-antigen-specific immune responses in the joint. Tolerizing DC + antigen may also be injected into joints, venous blood or lymphatics. Ag, antigen.