Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Oral delivery of Glutamic Acid Decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice (#194)

Sofie Robert 1 , Conny Gysemans 1 , Tatiana Takiishi 1 , Hannelie Korf 1 , Isabella Spagnuolo 2 , Guido Sebastiani 2 , Karolien Van Huynegem 3 , Lothar Steidler 3 , Silvia Caluwaerts 3 , Pieter Demetter 4 , Clive H Wasserfall 5 , Mark A Atkinson 5 , Francesco Dotta 2 , Pieter Rottiers 3 , Tom Van Belle 1 , Chantal Mathieu 1
  1. Department of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
  2. Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
  3. ActogeniX NV, Ghent-Zwijnaarde, Belgium
  4. Department of Pathology, Université Libre de Bruxelles (ULB), Brussels, Belgium
  5. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Florida, USA

Growing insight into the pathogenesis of type 1 diabetes 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 (L. lactis) bacteria for controlled secretion of the type 1 diabetes autoantigen GAD65370-575 and the anti-inflammatory cytokine IL10 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 nonobese diabetic (NOD) mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic T effectors, but increased the presence of CD4+Foxp3+CD25+ regulatory T cells (Tregs) with suppressive action in vitro as well as in vivo. These preclinical data indicate a great therapeutic potential of orally-administered autoantigen-secreting L. lactis for tolerance induction in type 1 diabetes.