Autoimmune diseases are the third leading cause of morbidity and mortality in France. The health stakes are high, especially as these are chronic diseases for which there is currently no specific immunosuppressive treatment capable of reducing the risk of complications of immunosuppressive treatments: infections and cancers. We do not yet know whether progress in understanding the pathophysiology of these diseases (see lectures 1, 3, 5) is likely to translate into therapeutic advances. Over the last sixty years, an arsenal of drugs has been developed, made up of immunosuppressive chemical molecules with different mechanisms of action, but all active in a non-specific manner, i.e. on both self-reactive and non-self-reactive lymphocytes. Over the past twenty years, a series of therapeutic monoclonal antibodies have been developed which act either by destroying B (or T) lymphocytes, or by neutralizing one or other effector molecule of the immune response. Their spectrum of efficacy varies, but their increasing use has considerably enriched the therapeutic arsenal, which is still based on very empirical principles. New perspectives are opening up, based on current experimental approaches, such as :
- converting effector cells into "harmless" cells, based on their physiological plasticity. This could be the case for modifying the behavior of TH17 effector T cells involved in numerous autoimmune or inflammatory pathologies;
- modulation of autoantigen presentation, for example by inhibiting translational modifications of proteins in dendritic cells, or by blocking activation of innate immunity receptors by "danger" signals (cellular debris, apoptotic bodies, etc.);
- inhibition of type 1 interferon, which may be involved in certain forms of disseminated lupus, by inhibiting its production, neutralizing it or chemically blocking its effects;
- amplification or induction of regulatory T cells, ideally specific to the autoantigens involved in a given autoimmune disease. The use of low-dose IL2 is a possible avenue currently being tested, as is the more cumbersome use of cell therapy consisting of in vitro-activated regulatory T lymphocytes.
Finally, the induction of tolerance by ectopic expression in the liver of an autoantigen obtained by gene transfer is an avenue being explored in animals, as is the generation of T lymphocytes capable of selectively destroying autoimmune B lymphocytes. These are multiple avenues of research, and their success will depend on how well they are adapted to our understanding of the pathophysiology of these diseases.
