Counteracting autoimmunity
Autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes are characterised by deregulated T cell function. T cell differentiation into T effector cells (Teff) or anti-inflammatory regulatory T cells (Treg) is governed by the concerted action of the co-stimulatory CD28 and CTLA-4 molecules. Emerging novel immunosuppressive therapies have been designed to target CD28 and CTLA4-mediated T cell activation using specific antagonists. However, this approach also eliminates Treg cells, which are invaluable components of the immune system. The EU-funded TRIAD (Tolerance restoration in autoimmune diseases by selective manipulation of the CD28 costimulatory pathway) study worked to correct T cell imbalance in autoimmunity by selectively inhibiting the differentiation of T cells into effector cells. In this context, they set out to improve the targeting of the CD28-CD80/86 axis implicated in Teff cell differentiation, and spare the Treg-associated CTLA4-CD80 interactions. As a first step, the consortium dissected the mode of action of selective CD28 antagonists. They discovered that these antagonists increase Treg suppressive function and reduce Teff cell responses. In vivo work further supported these observations, and also unveiled the implication of myeloid-derived cells in the tolerance-promoting capacities of CD28 antagonists. Testing of the CD28 antagonist FR104 in a non-human primate model produced promising results for experimental autoimmune encephalitis and collagen-induced arthritis. Treatment either alleviated the symptoms or completely abrogated disease onset. FR104 exhibited similar efficacy against skin inflammation and towards the maintenance of skin grafts in humanised animal models. However, a re-activation of a virus equivalent to Epstein-Barr was observed in a few treated animals, illustrating the need for careful investigation prior to initiating clinical trials. Overall, the results of the TRIAD study demonstrate the validity of selectively restoring self-tolerance as an approach to treating autoimmunity. The CD28 selective antagonists come as an improvement to current treatment options available for patients diagnosed with an autoimmune disease.
Keywords
Immune regulation, Treg cells, autoimmune diseases, CD28 antagonist, Immunotherapy
