Bacterial and plant enterotoxin B subunit-autoantigen fusion proteins suppress diabetes insulitis.
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.
Carter
James E
JE
Department of Biochemistry & Microbiology, Center for Molecular Biology and Gene Therapy, Loma Linda University, Loma Linda, CA 92354, USA.
Yu
Jie
J
Choi
Nak-Won
NW
Hough
John
J
Henderson
David
D
He
Darren
D
Langridge
William H R
WH
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001212:Asialoglycoproteins / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D002772:Cholera Toxin / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D060748:Fetuins; D005677:G(M1) Ganglioside / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D016233:Immunotherapy, Active / Q000379:methods; D007515:Islets of Langerhans / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000235:genetics; D011384:Proinsulin / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D012276:Ricin / Q000235:genetics / Q000276:immunology; D022621:Shiga Toxin / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014281:Trihexosylceramides / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism
D001212:Asialoglycoproteins; D001324:Autoantigens; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D060748:Fetuins; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D010446:Peptide Fragments; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D014281:Trihexosylceramides; D000509:alpha-Fetoproteins; C017029:asialofetuin; D005677:G(M1) Ganglioside; C018549:globotriaosylceramide; D022621:Shiga Toxin; D012276:Ricin; D002772:Cholera Toxin; D011384:Proinsulin; C027538:heat-labile enterotoxin, E coli; D005968:Glutamate Decarboxylase