par Robert, Sofie;Gysemans, Conny;Takiishi, Tatiana ;Korf, Hannelie;Van Belle, Tom L;Mathieu, Chantal;Spagnuolo, Isabella;Sebastiani, Guido;Dotta, Francesco;Van Huynegem, Karolien;Steidler, Lothar;Caluwaerts, Silvia;Rottiers, Pieter;Demetter, Pieter ;Wasserfall, Clive;Atkinson, Mark
Référence Diabetes (New York, N.Y.), 63, 8, page (2876-2887)
Publication Publié, 2014
Référence Diabetes (New York, N.Y.), 63, 8, page (2876-2887)
Publication Publié, 2014
Article révisé par les pairs
Résumé : | Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65370-575 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional β-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4+Foxp3 +CD25+ regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D. © 2014 by the American Diabetes Association. |