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

  1. Chantal Mathieu1,*
  1. 1Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium
  2. 2Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy
  3. 3ActoGeniX NV, Zwijnaarde, Belgium
  4. 4Department of Pathology, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
  5. 5Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
  1. Corresponding author: Chantal Mathieu, M.D., Ph.D., E-mail: chantal.mathieu{at}med.kuleuven.be

Abstract

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.

Footnotes

  • * T.L.V.B and C.M. share senior authorship

  • Received August 14, 2013.
  • Accepted March 24, 2014.

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  1. Diabetes
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