title: Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice.
abstract: Autoantigen-specific immunological tolerance represents a central objective for prevention of type 1 diabetes (T1D). Previous studies demonstrated mucosal antigen administration results in expansion of Foxp3+and LAP+regulatory T cells (Tregs), suggesting oral delivery of self-antigens might represent an effective means for modulating autoimmune disease. Early preclinical experiments using the non-obese diabetic (NOD) mouse model reported mucosal administration of T1D-related autoantigens [proinsulin or glutamic acid decarboxylase 65 (GAD)] delayed T1D onset, but published data are conflicting regarding dose, treatment duration, requirement for combinatorial agents, and extent of efficacy. Recently, dogma was challenged in a report demonstrating oral insulin does not prevent T1D in NOD mice, possibly due to antigen digestion prior to mucosal immune exposure. We used transplastomic plants expressing proinsulin and GAD to protect the autoantigens from degradation in an oral vaccine and tested the optimal combination, dose, and treatment duration for the prevention of T1D in NOD mice. Our data suggest oral autoantigen therapy alone does not effectively influence disease incidence or result in antigen-specific tolerance assessed by IL-10 measurement and Treg frequency. A more aggressive approach involving tolerogenic cytokine administration and/or lymphocyte depletion prior to oral antigen-specific immunotherapy will likely be required to impart durable therapeutic efficacy.
authors.affiliation: Departments of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Posgai
authors.affiliation: Departments of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Wasserfall
authors.affiliation: Department of Biochemistry School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kwang-Chul
authors.initials: KC
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Daniell
authors.affiliation: Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Desmond A
authors.initials: DA
authors.lastname: Schatz
authors.affiliation: Departments of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.|Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002772:Cholera Toxin / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007328:Insulin / Q000097:blood; D016688:Mice, Inbred NOD; D059828:Plant Cells / Q000378:metabolism; D018515:Plant Leaves / Q000378:metabolism; D030821:Plants, Genetically Modified; D018087:Plastids / Q000378:metabolism; D014026:Nicotiana / Q000378:metabolism*; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology*
chemical_list: D001324:Autoantigens; D007328:Insulin; D014612:Vaccines; D002772:Cholera Toxin; D005968:Glutamate Decarboxylase