Moving towards efficient therapies in type 1 diabetes: to combine or not to combine?

Abstract

Every year, thirty thousand people worldwide are diagnosed with type 1 diabetes mellitus (T1DM). T1DM, also called autoimmune diabetes, is a multifactorial disease affecting predisposed individuals and involving genetic susceptibilities, environmental triggers, as well as unbalanced immune responses. Auto-reactive T cells, produced during the pathogenesis, play an important role by specifically destroying the pancreatic insulin-producing beta-cells in the islets of Langerhans. Numerous therapeutic interventions have been tested, mostly in animal models, but also in humans. To date, only three phase II/III clinical trials have demonstrated safety and efficacy: anti-CD3 antibody, DiaPep277, and GAD65 (in patients with latent autoimmune diabetes in adults). Unfortunately, a significant number of patients did not respond positively and remained insulin-dependent after completion of therapy. Several reasons account for this. Firstly, the severity of the disease as well as the auto-aggressive T cell repertoire vary from patient to patient leading to a broad range of therapeutic efficacies, and secondly at the time of the treatment the number of remaining beta-cells will directly impact the level of insulin production post-treatment. In this review, we will provide some clues to enhance efficacy of future immuno-interventions in patients with T1DM. We suggest that combination therapies might be the best approach.

Figure 1. Combination therapy of anti-CD3 antibody and auto-antigenic immunizations efficiently dampens the auto-aggressive responses

A. Pathogenesis of type 1 diabetes. (1) In susceptible individuals, environmental triggers together with unbalanced immune responses cause the priming of auto-reactive effector T cells. (2) Auto-aggressive T cells infiltrate the islets of Langerhans and start destroying the insulin producing beta-cells via perforin- and cytokine-mediated cytotoxic mechanisms. (3) Auto-antigens (aAgs), such as insulin, GAD65 and others, are presented by antigen-presenting cells (APC) in the pancreatic lymph nodes (PLNs), (4) which enable the expansion of effector T cells and initiate epitope spreading. B. Blockade of type 1 diabetes by in-vivo expansion of antigen-specific regulatory T cells. (5) Immunization with various aAgs via a tolerogenic route (i.e mucosal) has been successful in inducing aAg-specific regulatory T cells (Tregs). (6) Systemic treatment with non-Fc binding anti-CD3 creates a therapeutic window by promoting a milieu for expansion of Tregs and by depletion of auto-reactive T cells. (7) Expanded aAg-specific Tregs migrate into the PLNs and dampen the auto-aggressive responses by bystander suppressive mechanisms.