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IMMUNOTHERAPY OF T1D Résumé de rapport

Project ID: 8659
Financé au titre de: FP6-MOBILITY
Pays: France

Final Activity Report Summary - IMMUNOTHERAPY FO T1D (Anti-CD3 systemic therapy in combination with antigen-specific intervention: A novel approach for treating type 1 diabetes)

Autoimmune diabetes, also called type 1 diabetes (T1D), results from an autoimmune attack destroying the pancreatic insulin-producing beta cells with a kinetic which may vary from patient to patient. Non-mitogenic anti-CD3 antibodies proved to be highly efficient in reversing recent onset T1D in animal models. Nevertheless, when tested in humans these antibodies lead to a temporal blockade of the beta-cell destruction, for up to two years, however permanent tolerance was never achieved and none of the patients treated with anti-CD3 reached normoglycemia without exogenous insulin. One of the mechanisms by which anti-CD3 mediates protection is the expansion of regulatory T cells (Tregs) in vivo by the creation of a 'regulatory' milieu.

On the contrary, vaccination with islet-autoantigens (aAgs) such as insulin, proinsulin and glutamic acid decarboxylase of 65 kDa (GAD65), was effective in preventing but unable to reverse new-onset T1D in animal models. Moreover, islet-aAg vaccines proved to be safer than anti-CD3 antibodies leading to some side-effects in humans. Interestingly, immunisation with islet-aAgs presents the property of inducing or expanding islet-specific Tregs. These cells possess the unique capacity to dampen polyclonal auto-aggressive responses without inducing general immunosuppression.

Therefore, we hypothesised that a synergy to treat new-onset T1D could be observed between anti-CD3 therapy and islet-aAgs immunisations. Consequently, we decided to combine both treatments to expand more forcefully islet-specific Tregs in vivo after new-onset diabetes and consequently increase the treatment efficacy.

We demonstrated that a novel combination treatment with anti-CD3epsilon-specific antibody and intranasal proinsulin peptide could reverse recent-onset diabetes in two murine models for T1D with much higher efficacy than with monotherapy with anti-CD3 or aAg alone. The expansion of insulin-specific Tregs was significantly enhanced in vivo. Thus, combining a systemic immune modulator, anti-CD3 in this case, with antigen-specific Treg induction was more efficacious in reverting diabetes. Since Tregs acted site-specifically, this strategy should also be expected to reduce the potential for systemic side effects.


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