TRIAD · Tolerance Restoration In Autoimmune Diseases by selective manipulation of the CD28 costimulatory pathway

The TRIAD, Tolerance Restoration In Autoimmune Disease, consortium provides an innovative strategy to autoimmune diseases (AID) therapy, based on antibody approach with a well established mechanism of action. The main objective is the evaluation of a selective antagonist of CD28 to prevent, treat and/or cure some AIDs in preclinical models including rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis, uveitis and arteriosclerosis.The concept is based on rather than suppressing the immune system as a whole, suppressing only the parts of the immune system responsible for the autoimmune attack, while sparing and enhancing regulatory T cells. Costimulation through the CD28/B7/CTLA-4 molecular triad controls the balance effector/regulatory functions after initial antigen exposure. An antagonist anti-CD28 represents a novel drug candidate allowing very specific immunosuppression compatible with regulatory T cells function, immune regulation and therefore tolerance induction/restoration.The TRIAD project will start with the study of the efficacy of a new selective antagonist of CD28 in non-human primate models and the exploration of the potential efficacy of surrogate CD28 antagonist in rodent models. Then will be performed an evaluation of potential immunological toxicity of the antagonist in humanized SCID mice and non-human primate, to exclude agonist activity in vivo. Previously identified mechanisms of action (i.e. costimulation blockade and induction of Tregs) in the context of AID will be confirmed in experimental models. Formulation and preclinical toxicological studies will be run before initiating PhaseI/II trial in patients.TRIAD capitalises on the strong experience available in Brazil and Europe in the field of immunology. It comprises 6 academic institutions and 1 SME being the coordinator of the 3-year project. International cooperation with project is ensured by the integration of a leading Brazilian research centre in the consortium.""