title: Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice.
abstract: 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.
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Robert
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Takiishi
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Hannelie
authors.initials: H
authors.lastname: Korf
authors.affiliation: Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Spagnuolo
authors.affiliation: Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Sebastiani
authors.affiliation: ActoGeniX NV, Zwijnaarde, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Van Huynegem
authors.affiliation: ActoGeniX NV, Zwijnaarde, Belgium.
authors.forename: Lothar
authors.initials: L
authors.lastname: Steidler
authors.affiliation: ActoGeniX NV, Zwijnaarde, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Caluwaerts
authors.affiliation: Department of Pathology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Demetter
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.affiliation: Diabetes Unit, Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena and Fondazione Umberto Di Mario ONLUS, Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dotta
authors.affiliation: ActoGeniX NV, Zwijnaarde, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Rottiers
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Van Belle
authors.affiliation: Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium chantal.mathieu@med.kuleuven.be.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000284:Administration, Oral; D000375:Aging; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D013294:Lactococcus lactis; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C000592122:GAD65(370-575), human; D010446:Peptide Fragments; D016753:Interleukin-10; D005968:Glutamate Decarboxylase