globotriaosylceramide and Diabetes-Mellitus--Type-1

Several bacterial and plant enterotoxin B subunit-islet autoantigen fusion proteins were compared for their ability to serve as islet autoantigen carriers and adjuvants for reduction of pancreatic islet inflammation associated with type 1 diabetes. The cholera toxin B subunit (CTB), the heat-labile toxin B subunit from enterotoxigenic Escherichia coli (LTB), the Shigella toxin B subunit (STB), and the plant toxin ricin B subunit (RTB) were genetically linked to the islet autoantigens proinsulin (INS) and glutamic acid decarboxylase (GAD). The adjuvant-autoantigen gene fusions were transferred to a bacterial expression vector and the corresponding fusion proteins synthesized in E. coli. The purified adjuvant-autoantigen proteins were fed to 5-wk-old nonobese diabetic (NOD) mice once a week for 4 wk. Histological examination of pancreatic islets isolated from inoculated mice showed significant levels of insulitis reduction in comparison with uninoculated mice. The ratio of serum anti-INS and anti-GAD IgG2c to IgG1 antibody isotype titers increased in all ligand-autoantigen inoculated animal groups, suggesting an increase in effector Th2 lymphocytes in B subunit-mediated insulitis suppression. The results of these experiments indicate that bacterial and plant enterotoxin B subunit ligand-autoantigens enhance insulitis reduction in NOD mice. This research prompts further exploration of a multiadjuvant/autoantigen co-delivery strategy that may facilitate type 1 diabetes prevention and suppression in animals and humans.

Topics: alpha-Fetoproteins; Animals; Antibody Formation; Asialoglycoproteins; Autoantigens; Bacterial Toxins; Cholera Toxin; Diabetes Mellitus, Type 1; Enterotoxins; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Escherichia coli Proteins; Female; Fetuins; G(M1) Ganglioside; Glutamate Decarboxylase; Immunoglobulin G; Immunoglobulin Isotypes; Immunotherapy, Active; Islets of Langerhans; Mice; Mice, Inbred NOD; Peptide Fragments; Proinsulin; Protein Subunits; Recombinant Fusion Proteins; Ricin; Shiga Toxin; Trihexosylceramides