Exploring combination therapy to optimise costimulation blockade in autoimmunity

Costimulation blockade is a widely used strategy to dampen T cell responses in the setting of autoimmunity.

It slowed beta-cell destruction when trialled in individuals with new onset type 1 diabetes (T1D), however benefits were deemed insufficient to support routine use of this therapy.

One drawback of inhibiting CD28 costimulation is that this same pathway is also needed to support regulatory T cell (Treg) homeostasis. Thus, at the same time as inhibiting pathogenic T cells, the treatment also reduces Treg numbers. This undesirable side-effect impairs natural immunosuppression. We have found that this limitation can be offset by combining costimulation blockade with low dose IL-2 therapy.

The resulting combination therapy supports Treg homeostasis while retaining inhibition of pathogenic T cell responses. Preliminary data suggest this combination therapy is highly effective at inhibiting diabetes in a mouse model.

We now wish to follow up these exciting findings to understand key mechanistic questions about this therapy and its potential utility. Are the Treg that are rescued in this manner equivalent to normal Treg in their phenotype and suppressive properties? Is the therapy still effective if administered after diabetes has developed?

Our findings could lead to a new approach for therapeutic intervention in T1D.