MIRASLE

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are severe autoimmune diseases characterized by the production of pathogenic autoantibodies leading to inflammation and organ damages. Current treatments reduce inflammation but have significant side effects and are not curative. Since autoreactive B cells and differentiation into plasma cells secreting pathogenic autoantibodies play a central role in SLE and RA, one promising and more specific therapeutic strategy would be to target autoreactive B cells and particularly long-lived IgG memory B cells. This is the main strategy chosen by the partners to develop new immunotherapies for these diseases. However, the lack of suitable preclinical models limits the development and evaluation of such immunotherapies. While existing mouse models partially replicate disease symptoms, their non-human immune system does not accurately mimic human autoimmune responses. Therefore, the development of humanized models is essential to validate new human-specific immunomodulatory agents. A recently developed model based on immunodeficient mice engrafted with CD34+ hematopoietic stem cells (HSCs) and treated with 17ß-estradiol (E2) effectively replicates human lymphoid and myeloid compartments, including functional B lymphocytes. This model provides an advanced and powerful platform for in vivo studies of human immune responses, and particularly antibody and autoantibody responses, therefore presents a valuable opportunity to study SLE and RA pathogenesis and evaluate new immunotherapies. Our project aims to develop two highly relevant experimental humanized animal models, mimicking SLE and RA respectively, based on this advanced platform. To develop these models, the partners selected similar immunodeficient mice, with genetic background that closely aligns with the models used, but commercially available in France. The first experimental model developed in our project will be the pristane-E2-treated-humanized mice that develop a series of clinical and immunological manifestations that mirror human SLE, including the production of autoantibodies, the development of skin lesions and renal manifestations. We will thoroughly characterize the clinical and immunological manifestations of this model mimicking human SLE. The second experimental model will be a novel DR4-humanized E2-treated mice model, immunized with specific peptides, such as citrullinated peptides conjugated with KLH, to induce the production of ACPA to trigger the pathogenesis of RA. Once established and fully characterized, these models will enable the evaluation of innovative therapeutic approaches targeting antigen-specific B lymphocytes in vivo using novel experimental molecules. Two approaches will be assessed: first, the development of an anti-idiotype uniquely found in SLE, and second, the testing of Ag-Fc fusion molecules, adapted according to the frequency of autoreactive B cells. These advanced humanized models will enable more accurate preclinical evaluation of therapies for SLE and RA, potentially reducing failure rates in clinical trials. Additionally, they could serve as platforms for testing other types of immunotherapies, benefiting both patients and drug development.