Based on results of early-stage clinical trials, antigen-specific tolerizing immunotherapy has therapeutic potential for autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, and other seropositive autoimmune diseases, according to a series paper published in Lancet Rheumatology.
According to the authors, patients rarely achieve drug-free remission after diagnosis, often due to impaired immune self-tolerance. Despite the ability to recognize at-risk individuals through genotyping, antibody tests, and symptom assessment, RA cannot yet be successfully prevented.
“The ideal management of [RA] would be disease prevention or long-lasting drug-free remission,” the authors wrote. “These methods would require a safe, durable, and specific intervention to suppress autoimmune responses selectively, while leaving the rest of the immune system functionally active for control of infectious and tumor antigens.”
Although these methods do not currently exist, precision medicine modalities may provide the necessary proof-of-concept that these goals may be achievable.
In a review of the potential approaches demonstrating the proof-of-concept for antigen-specific tolerizing immunotherapy for autoimmune diseases, a key aspect discussed was the disease stage at which the intervention should be performed. The success of tolerance-based approaches is likely to be highest among patients with new-onset RA or those at risk, and lower among patients with long-term suboptimal disease control. These tolerizing strategies are likely to require concomitant symptom control with either synthetic or biologic disease-modifying antirheumatic drugs.
The development of antigen-specific immunotherapies requires an understanding of which antigens should be targeted in each individual autoimmune disease, along with a decision about antigen format: single or multiple peptide epitopes; pMHC complexes; whole proteins or protein fragments; or RNA or DNA. Injection route and dose both influence antigen immunogenicity. Currently, the selection of suitable antigens for tolerizing immunotherapy remains a challenge; antigenic targets differ in number between diseases, and environmental autoimmune diseases present with variable antigenic hotspots and autoantibody specificities.
In RA, an autoimmune response is characterized by multiple T- and B-cell epitopes. Anticitrullinated protein antibody (ACPA) autoimmunity — observed in 70% of patients with RA — is highly cross-reactive, and data suggest that epitope reactivities “do not identify an initiating antigen.” One conceptual framework suggests that ACPA-producing B cells can survive and expand only with the help of T cells. These T cells are not representative of a single antigen and are not specific for citrullinated epitopes.
Multiple approaches have been proposed and used to identify potential synovial autoantigens in RA, including immunoaffinity purification of the human leukocyte antigen – DR isotype (HLA-DR) molecules and mass spectrometry identification of eluted peptides. Advances in these areas have enhanced the discovery of citrullinated autoantigenic targets in RA. Potential candidate RA autoantigens include aggrecan; type II collagen; human cartilage glycoprotein 39; and multiple citrullinated peptides associated with neutrophil extracellular trap, including H4-39Cit33-47, oral heat shock protein, and heterogeneous nuclear ribonucleoprotein A2.
“Despite the specificity of ACPA for seropositive [RA], the inherent cross-reactivity of ACPA towards linear epitopes, and the broad spectrum of observed T-cell reactivities reinforce the concept that no single dominant autoantigen exists,” the authors concluded. “However, this limitation opens up opportunities for restoring tolerance before and at onset of [RA], with antigen-specific immunotherapy using  or more of the described epitopes to drive bystander suppression.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Nel HJ, Malmström V, Wraith DC, Thomas R. Autoantigens in rheumatoid arthritis and the potential for antigen-specific tolerising immunotherapy. Lancet Rheumatol. 2020;2:e712-e723.