Resuscitating adaptive Tregs with combination therapies?

Induction of 'adaptive' regulatory T cells (Tregs) using islet-specific antigen vaccinations has been shown to prevent disease in various animal models for type 1 diabetes (T1D). Even though translation from bench to bedside has been unsuccessful so far, this non-invasive approach is the Holy Grail to safely achieve immune tolerance in humans. We will discuss here the fact that every immune response appears to contain a balance of adaptive effector and Treg cells. The evolution of these population and their antigen specificities over time during diabetes development will determine at which time and route a given islet antigen can be chosen to augment such adaptive Tregs most efficiently. Their 'resuscitation' will be crucial for long-term tolerance and homeostasis in the islet micro-environment, which is ultimately needed for a cure from T1D. Recent insight from our studies shows that short-term creation of a systemic milieu that favours Treg propagation, as it occurs after systemic administration of non Fc-binding anti-CD3, can strongly enhance this process. We propose that combination therapies with anti-CD3 or similar systemic immune modulators that lower effector cells and enhance Tregs with vaccines that induce adaptive Tregs will be a crucial step in developing successful immune-based intervention in T1D.