Immunotherapy in Type 1 Diabetes: A Shorter but More Winding Road?

We strive but struggle to translate immune therapies that have been shown to be effective in preclinical models of autoimmune diabetes into use with patients. Only a small proportion of these therapies are actually tested in humans, and of these, efficacy (even short-term) has been achieved in less than a handful (1). A striking example of this struggle is provided by a clinical trial reported in the current issue of Diabetes (2). After setting everything up correctly with convincing data in preclinical models (3,4), an attractive hypothesis (5), and safety studies in animals, the Immune Tolerance Network (ITN) conducted a single-arm trial of combination therapy with interleukin (IL)-2 (4 weeks) together with rapamycin (12 weeks) in patients who had recently developed type 1 diabetes. Treatment successfully led to a respectful increase in circulating regulatory T cell (Treg) numbers. However, the therapy failed to halt β-cell loss and even transiently exacerbated loss of β-cell function. Interestingly, IL-2 seems to have been responsible for both the increased Treg numbers and the loss of β-cell function. It also seems that IL-2 acted on effector arms of innate immunity and that this may have led to the negative effects on the β-cell.

The rationale for IL-2 therapy in type 1 diabetes is relatively strong (Fig. 1), with reproducible genetic associations with genes of the IL-2 pathway (6) and functional defects in IL-2 signaling (7–9), plus successful use of IL-2 in preclinical models of autoimmune diabetes (3,4) and therapeutic benefit in patients with immune-mediated disorders (10,11). One can always find ways to be …