Antigen-specific immunotherapies in rheumatic diseases

Abstract

The main goal of antigen-specific immunotherapy (ASI) in autoimmune and rheumatic diseases is to reprogramme or remove autoreactive cells and/or induce immune tolerance to self-antigens. Current therapies in these diseases either treat symptoms or slow down disease progression but are not yet curative or preventative - disease-specific treatments are urgently needed. In contrast to the nonspecific treatments in current use that induce generalized immune suppression, which is associated with several adverse effects including increased risk of infections, ASIs target a restricted subset of B cells or T cells, and thus do not compromise systemic immunity and host defence. This Review provides a summary of novel approaches for identifying autoepitopes and detecting and targeting autoreactive cells that might help in the development of ASIs. Promising approaches include the use of tolerizing peptides coupled to MHC constructs and/or nanocompounds, tolerizing dendritic cells and antigen-specific vaccines. Following studies in animal models of rheumatoid arthritis and systemic lupus erythematosus, several of these strategies have now entered clinical trials. However, to use these approaches in humans, several important limitations must first be addressed, such as; selecting the proper immunodominant autoantigen; identifying the optimal timing, dosing and route of administration; finding biomarkers for monitoring the therapy; and optimizing methodology.

Transfer of antigen-encoding bone marrow under immune-preserving conditions deletes mature antigen-specific B cells in recipients and inhibits antigen-specific antibody production

“…For example, tolerising T and B cells has been shown to halt or reverse disease progression in some preclinical models of antibody-mediated disease (Pozsgay, Szekanecz et al 2017), lending credence to this suggestion. It does, however, remain to be directly determined whether responsiveness of memory B cells is limited by transfer of antigen-encoding BM.…”

Peptide-Based Vaccination Therapy for Rheumatic Diseases

“…Additionally, disease heterogeneity is a well-defined characteristic of rheumatic diseases, and the immunodominant pathogenic epitopes are different across patients with distinct disease stages or clinical characteristics, which can limit the therapeutic efficacy of vaccinations targeting a small part of epitopes. Neoepitopes originating from epitope spreading or modified epitopes can further increase disease heterogeneity [65]. Therefore, personalized peptide vaccinations may be a more adequate approach for developing effective vaccination therapy against rheumatic diseases, in which peptides for targeted vaccinations are specifically selected for each individual patient.…”

“…It has been well defined that vaccination with an entire antigen or key tolerogenic peptides in the absence of adjuvant or costimulation signals has the potential to induce antigenspecific immune tolerance, which is a potentially effective approach in treating autoimmune diseases [62][63][64]. Therefore, modulation of the pathogenic immune response through antigen-specific tolerogenic vaccination has the potential to restore immune tolerance and ameliorate autoimmune attacks in rheumatic diseases [62,65]. Most of those studies were based on animal models of autoimmune diseases, while relevant clinical studies are still limited.…”

Autoreactive B‐lymphocytes in SLE and RA patients: Isolation and characterisation using extractable nuclear and citrullinated antigens bound to immunobeads

“…Ectopic lymphoid foci often develop, behaving as sources of ABLs and ASCs that migrate and accumulate in damaged organs and tissues where they receive signals for survival and maturation [8][9][10][11][12][13]. Therefore, B lymphocytes and ASCs are considered relevant targets for therapy in SLE and RA patients [14][15][16][17].…”