TRIAD

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

A European consortium is developing a novel therapeutic intervention for autoimmune diseases. This approach specifically suppresses the immune system parameters responsible for the autoimmune attack, while enhancing regulatory T cells.

Descrizione progetto (Article)

Deregulated T cell function is a characteristic of autoimmune diseases including rheumatoid arthritis, multiple sclerosis and type 1 diabetes. During T cell activation, co-stimulatory molecules regulate their differentiation into T effector or anti-inflammatory T cells. The balance between these two types of T cells is achieved by the concerted action of CD28 and CTLA-4.

Targeting the CD28-mediated T cell activation with antagonists (CD80/86) has proven to be a promising alternative to current immunosuppressive treatments. However, this strategy inhibits the entire pathway including CTLA-4 signals that are crucial to the function of regulatory T cells.

The EU-funded http://www.triad-cd28.eu/ (TRIAD) project proposes to correct T cell imbalance through selective inhibition of CD28. This approach promises to restore or induce peripheral tolerance.

In this context, researchers are screening a novel CD28 antagonist (FR104 antibody) in non-human primate and rodent models for toxicity and efficacy. In vitro studies show that antagonising CD28 increases regulatory T cell suppressive activity and reduces effector T cell responses.

Promising results have also been obtained in a macaque model of collagen-induced arthritis. In vivo administration of the anti-CD28 antibody seems to abrogate arthritis symptoms and prevent inflammation. Interestingly, the CD28 blockade could also be applied for prolonging allograft survival.

Dampening the activation of T effector cells could potentially reactivate endogenous viruses such as Epstein-Barr virus. This demonstrates the need for careful investigation prior to initiating clinical trials. Nonetheless, the TRIAD concept of selectively restoring self-tolerance to treat autoimmunity constitutes a valid approach.