Counteracting autoimmunity

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 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.