The Quest for Antigen-Specific Therapy in RA

There are currently no therapies that have achieved antigen-specificity for controlling symptoms in rheumatoid arthritis.

Approximately 30% of RA patients do not achieve sustained remission or restoration of self-antigen immune tolerance with existing disease-modifying and biologic therapies, drugs which often fail or carry toxicity (i.e., risk of infection). So patients must frequently endure life-long treatment.

Research into superior approaches has so far been stymied by inadequate knowledge of the pathogenesis of this autoimmune disease and of specific RA autoantigens, as well as the exact mechanisms of human immune tolerance. However, we are now moving closer to our goal of developing more effective immunotherapies, using tolerance-inducing antigen-specific strategies and dendritic cells (illustrated above).

The outcome holds great promise for achieving greater drug specificity with lower toxicity -- and the potential for agents to control or even prevent RA. The market for such new therapies is predicted to grow to $12 billion annually by 2017.

Key research developments, as outlined in my recent review¹ on this topic, include:

 •   Anti-citrullinated peptide antigens (ACPA) have emerged as a valuable biomarker in RA, possibly predating its onset by as long as 15 years. Approximately 70% of RA patients have sera containing autoantibodies reactive to a variety of ACPAs. Post-translationally modified peptides may represent an important means to diversify the repertoire of antigens (and responding T cells) in reaction to inflammatory or stressful events such as infections, and thus may have some therapeutic potential.

•   Injecting dendritic cells (DCs) for antigen-specific tolerance. Active mechanisms of peripheral tolerance include deletion of self-reactive cells after antigen recognition and regulation of self-reactive effector responses by specialized populations of regulatory T cells (Tregs). Injecting antigen-presenting DCs could induce antigen-specific Tregs, which in turn may suppress RA self-antigen-specific immune responses in the joint itself.

•   Clinical trials of oral tolerization. A bacterial heat shock protein sequence, dnaJp1 peptide, has been proposed to be cross-reactive with corresponding self-peptides in RA. In phase I and II clinical trials, oral dnaJp1 peptide demonstrated an excellent safety profile and immune modulatory effects.

•   Targeting dendritic cells for antigen-specific tolerance. In a mouse model of rheumatoid arthritis, liposomes loaded with antigenic protein and a natural anti-inflammatory and antioxidant (curcumin) were delivered subcutaneously to target dendritic cells in draining lymph nodes. This induced antigen-specific Tregs (among other regulatory responses), suppressing effector T-cell responses and the clinical signs of full-blown antigen-induced arthritis.

Demonstrating the safety and efficacy of antigen-specific immunotherapeutic strategies such as these in early established RA would be an important first step toward preventive approaches in genetically at-risk individuals or families.