Combination Therapies for Type 1 Diabetes: Why Not Now?

Abstract

Type 1 diabetes (T1D), often referred to as juvenile diabetes, is thought to be an autoimmune disease in which insulin-producing b-cells in the islets of Langerhans of the pancreas are being destroyed, resulting in hyperglycemia and the need for lifelong insulin injections. In addition to the impact on quality of life, life-threatening long-term complications can be caused by high blood sugar levels, which predominantly affect the vasculature, resulting in increased risk for heart attacks, strokes, kidney failure, blindness and reduced overall life expectancy. The disease is caused by a complex interplay of genetic and environmental factors and, since the precise cause is not known and the human pancreas is difficult to access, development of an immunotherapy has been slow. However, we have learned important lessons in recent years that should strongly impact upon future therapeutic decisions and, as proposed in this editorial, now lead us to prioritize testing the rationale of combination therapies in clinical trials. The foremost insight is that T1D, even after successful reversal with cyclosporine or nonmyeloablative stem cell therapy (both of which have considerable systemic side effects and, therefore, could not be applied as a generalized intervention) has the unfortunate tendency to recur [1,2]. This is due to the accumulation of b-cell antigen-specific memory T cells, which can expand and react more efficiently, as soon as b-cells are being augmented or reintroduced. This was elegantly demonstrated in recent islet transplantation trials in which the amount of preexisting autoimmune cells positively correlated with the rapidity of graft loss within 2–4 years [3]. In addition, earlier studies by Sutherland had demonstrated that islets within the pancreas of a nondiabetic twin transplanted into his diabetic sibling were destroyed within months by a recurrent autoimmune attack [4], demonstrating that even new syngeneic b-cells generated from autologous stem cells would be rapidly annihilated. These facts underline the need for devising a form of immunotherapy that can create longterm tolerance to b-cells while circumventing unacceptable side effects from chronic immunosuppression, most notably secondary cancers [5]. Thus, since there is little proof to date that a onetime resetting intervention can eliminate, control or decimate the autoreactive memory pool sufficiently, our options for monotherapies are rather limited at present [6].