Oral delivery of Glutamic Acid Decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice
- Sofie Robert1,
- Conny Gysemans1,
- Tatiana Takiishi1,
- Hannelie Korf1,
- Isabella Spagnuolo2,
- Guido Sebastiani2,
- Karolien Van Huynegem3,
- Lothar Steidler3,
- Silvia Caluwaerts3,
- Pieter Demetter4,
- Clive H. Wasserfall5,
- Mark A. Atkinson5,
- Francesco Dotta2,
- Pieter Rottiers3,
- Tom L. Van Belle1,* and
- Chantal Mathieu1,*⇑
- 1Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium
- 2Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
- 3ActoGeniX NV, Zwijnaarde, Belgium
- 4Department of Pathology, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
- 5Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
- Corresponding author: Chantal Mathieu, M.D., Ph.D., E-mail:
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 in an efficient and safe manner. 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 effector T cells, but increased the presence of functional CD4+Foxp3+CD25+ regulatory T cells (Tregs). These preclinical data indicate a great therapeutic potential of orally-administered autoantigen-secreting L. lactis for tolerance induction in type 1 diabetes.
* T.L.V.B and C.M. share senior authorship
- Received August 14, 2013.
- Accepted March 24, 2014.
- © 2014 by the American Diabetes Association.
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