Biologia Futura: Emerging antigen-specific therapies for autoimmune diseases

Abstract

Autoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences of autoimmune diseases have increased significantly worldwide over the last decades; nearly 5% of the world's population is affected. The current treatments aim to reduce pain and inflammation to prevent organ damage and have a general immunosuppressive effect, but they cannot cure the disease. There is a huge unmet need for autoantigen-specific therapy, without affecting the immune response against pathogens. This goal can be achieved by targeting autoantigen-specific T or B cells and by restoring self-tolerance by inducing tolerogenic antigen-presenting cells (APC) and the development of regulatory T (Treg) cells, for example, by using autoantigenic peptides bound to nanoparticles. Transferring in vitro manipulated autologous tolerogenic APC or autologous autoantigen-specific Treg cells to patients is the promising approach to develop cellular therapeutics. Most recently, chimeric autoantibody receptor T cells have been designed to specifically deplete autoreactive B cells. Limitations of these novel autoantigen-specific therapies will also be discussed.

“Untargeting” autoantibodies using genome editing, a proof-of-concept study

“…In alignment with the concept of precision medicine, the therapy of autoimmune patients should address specific autoantigen systems and deranged immune-metabolic pathways at the individual level. This approach may be feasible with recent technologies, such as the Chimeric autoantibody receptor T cell (CAART), or the affinity matrix (AM), among others [11],…”

“…Ablation of specific B/plasma-cell clones in autoimmune diseases caused by pathogenic autoantibodies would greatly improve treatment, thus scientists worldwide have proposed a variety of strategies. We will mention two recent experimental strategies to achieve such an endeavor, although there are several others [11].…”

Suppression of Autoimmune Rheumatoid Arthritis with Hybrid Nanoparticles That Induce B and T Cell Tolerance to Self-Antigen

“…Many if not most autoimmune diseases involve antibodies to self-antigens that mediate disease pathology. − Some of the most promising strategies for treating the cause of these diseases directly or indirectly target either B cells or T cells involved in the production of autoimmune antibodies. ,− B cell depletion via CD20-targeting monoclonal antibody rituximab has been FDA approved to treat rheumatoid arthritis and pemphigus and is being evaluated for treatment of many other autoimmune diseases such as SLE. ,− While remission of symptoms in pemphigus is achieved in most patients, relapses occur when B cells are replenished, requiring additional rounds of treatment. , T cell directed therapies include depletion of T cells at the induction/expansion of tolerogenic Tregs that suppress immune responses. ,, For example, administration of low doses of interleukin 2 to expand Tregs has shown promise in the treatment of systemic lupus erythematosus (SLE) and type I diabetes . Cellular therapies using CD19-CAR T cells to deplete B cells or administering expanded Tregs are also beginning to show promise in clinical trials. − …”

“Untargeting” Autoantibodies Using Genome Editing, a Proof-of-Concept Study

“…In alignment with the concept of precision medicine, the therapy of autoimmune patients should address specific autoantigen systems and deranged immune-metabolic pathways at the individual level. This approach may be feasible with recent technologies, such as the Chimeric autoantibody receptor T cell (CAART), or the affinity matrix (AM), among others [11], including the CRISPR/Cas-based genome editing used in this study. With such approaches, the immune system could be modulated, suppressed, or enhanced, aiming to tolerate or attack specific autoantigens in the scenarios of autoimmunity and cancer, respectively.…”