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Title: Oral delivery of Glutamic Acid Decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice
Authors: Robert, Sofie
Gysemans, Conny
Takiishi, Tatiana
Korf, Hannelie
Spagnuolo, Isabella
Sebastiani, Guido
Van Huynegem, Karolien
Steidler, Lothar
Caluwaerts, Silvia
Demetter, Pieter
Wasserfall, Clive H
Atkinson, Mark A
Dotta, Francesco
Rottiers, Pieter
Van Belle, Tom #
Mathieu, Chantal # ×
Issue Date: Aug-2014
Publisher: American Diabetes Association
Series Title: Diabetes vol:63 issue:8 pages:2876-2887
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.
ISSN: 0012-1797
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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