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Anti-CD3 systemic therapy in combination with antigen-specific intervention: A novel approach for treating type 1 diabetes


Type 1 diabetes (T1D) is thought to be T-cell mediated auto-immune disease, where auto-aggressive CD4+ and CD8+ lymphocytes target and destroy the insulin producing pancreatic b-cells. During the last decade several studies focused on different immune-based therapies to treat or prevent T1D.

Numerous data point towards two promising immune interventions:
(1) The antigen specific prevention of T1D for example with DNA vaccines, proinsulin, GAD and insulin B chain, which can prevent T1D in more than 50% RIP-L CMV transgenic or NOD mice. Unfortunately, the protective effect of such strategies was only observed when the antigen was given early during the prediabetic phase.
(2) In contrast, non-mitogenic anti-CD3 antibody is able to revert recent-onset TID in NOD m ice, which was initially discovered by Lucienne Chatenoud. This antibody has already been tested by Jeff Bluestone and Kevan Herold clinically and preserved C-peptide levels over the first year in recent-onset diabetics.

The aim of our present study is based on the idea that combination of anti-CD3 systemic therapy with antigen specific approaches might result in a synergistic effect. We believe that anti-CD3 will act to "reset" the immune system, then leaving a window for therapeutic intervention with anti gen specific treatments to induce regulation that can maintain long-term tolerance in T1D.

This approach will be tested pre-clinically by using the NOD and RIP-LCMV transgenic mouse models treated with a commercial anti-CD3 Fab'2 in combination with islet specific-antigens (administered as DNA, peptides or full protein) after recent onset of T1D. In our opinion, this strategy will increase efficacy of antigen specific immunizations by opening a window for re-direction of the existing autoreactive response and/or de novo induction of autoantigen specific (adaptive) regulatory T cells. We believe the risk for adverse allergic reactions as well as aggravation of the autoimmune process will be lowered through.

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