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, Katholieke Universiteit 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, Brussels, Belgium
- 5Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
- Corresponding author: Chantal Mathieu, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1236/-/DC1.
T.L.V.B. and C.M. share senior authorship.
See accompanying article, p. 2603.
- Received August 14, 2013.
- Accepted March 24, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.