Damien Bresson, Yulia Manenkova and Matthias von Herrath (Principal Investigator)
Antigen-based immuno-interventions are potent therapies to induce antigen-specific regulatory T cells (Tregs) when administered under tolerogenic conditions among which antigen dosage, route and timing of administration play a major role. In type 1 diabetes (T1D) administration of islet-autoantigens (aAgs), such as (pro)insulin, glutamic acid decarboxylase of 65-kDa (GAD65) or others into pre-diabetic animal models of T1D was shown to induce islet-specific Tregs and prevent the disease. The advantage of this strategy is that it avoids general immunosuppression and acts as a site-specific drug in the pancreas or the pancreatic lymph nodes (PLNs). Antigen-induced Tregs can dampen multiple auto-aggressive responses through a mechanism called bystander suppression, precluding the need to precisely identify the specificity of the autoaggressive lymphocytic populations. However, aAg immunizations are often inefficient when tested into newly-diabetic animals. Our goal is to develop new strategies to strengthen antigen-based therapies and cure T1D after new-onset.
Several studies reported the capacity of anti-CD3 monoclonal antibodies (mAb) to reverse new-onset TID. They can achieve T cell tolerance by inducing a partial or altered signal through the CD3 pathway which differentially affects Tregs (expansion) and effector T cells (deletion/anergy). Anti-CD3 therapy results in permanent remission in mice and arrests the deterioration of insulin production in the majority of treated patients. Even though, anti-CD3 mAb constitutes a real breakthrough in the therapy of T1D, a single course treatment does not induce permanent remission in humans.
We hypothesized that treatment of recent-onset T1D could be improved by the combination of anti-CD3 and islet-derived vaccines. We published in 2006 that a short-course systemic injection of low doses anti-CD3 antibody in conjunction with proinsulin peptide immunizations was able to cure T1D after new-onset in two animal models (Bresson D et al. J. Clin. Invest. 2006). This CT was more efficacious than both treatments given alone and efficacy was driven by the expansion of proinsulin-specific regulatory T cells (Tregs) which was further increased when anti-CD3 antibody and proinsulin were combined. More recent studies lead to the finding that genetic background can influence the capacity to generate a protective autoantigen (aAg)-specific Tregs response after CT. Our data demonstrated that the aAg-specific (CD4+) T cell repertoire available at diabetes onset and shaped by differential expressions of various HLA/MHC molecules can drive the number and specificity of islet-specific Tregs expanded after CT (Bresson D et al. Mol. Therapy 2009). Our findings hold important implications to understand and predict success of antigen-based clinical trials, where responsiveness to immunotherapy might vary from patient to patient.