Immunotherapy after recent-onset type 1 diabetes: combinatorial treatment for achieving long-term remission in humans?

Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes mellitus (T1DM), is one of the most common autoimmune diseases. This chronic disorder is thought to be caused by auto-aggressive T lymphocytes that enter the pancreatic islets of Langerhans, where they destroy the insulin-producing β-cells. Activation of such cells is probably multi-factorial involving a genetic predisposition [1], environmental triggers [2] such as viruses and perhaps direct damage to the pancreas itself (pancreatic β-cells), for example, caused by a local pro-inflammatory reaction. Since the β-cell destruction is usually advanced when pre-diabetic human individuals are identified by screening for islet-cell antibodies, one can assume that aggressive responses to more than one islet-antigen will be ongoing during this stage of the disease [3]. It is, therefore, not necessarily practical to attempt to anergize or delete all of the auto-aggressive lymphocytes using direct antigen-specific immunotherapy with all of their cognate antigens. Furthermore, strong forms of non-specific systemic immunosuppression are not usually acceptable, since diabetes frequently affects young individuals, and insulin substitution affords a reasonable quality of life. However, insulin cannot prevent all of the late complications of diabetes, and life expectancy is usually reduced by 10 to 15 years [4]. Therefore, a curative immune-based intervention, with low systemic side-effects, which is able to reverse the course of the disease after recent onset is very desirable. One attractive possibility is the antigen-specific induction of auto-reactive regulatory cells (Treg) that can act as ‚bystander suppressors’ and simultaneously dampen multiple auto-aggressive T cells with heterogeneous specificities. However, in order to bring such a strategy closer to a potential application in humans, several obstacles still have to be overcome. Indeed, it is not precisely known (i) what effector mechanisms are used by autoreactive regulatory cells; (ii) how to safely choose the appropriate autoantigen suited for antigen-specific immune intervention; or (iii) how to optimize the efficacy of such immunotherapy.