Glutamic acid decarboxylase epitope protects against autoimmune diabetes through activation of Th2 immune response and induction of possible regulatory mechanism.
Oral tolerance mediated by autoantigens has been applied successfully as a potential therapeutic strategy for preventing and treating autoimmune diseases. We previously showed cholera toxin B subunit (CTB) is an efficient mucosal carrier molecule for induction of systemic T cell tolerance to linked insulin antigens. In this study, we used an oral antigen consisting of a fusion protein composed of CTB and triple copies of glutamic acid decarboxylase 65 (GAD65) peptides 531-545 (3p531) to test its in vivo effect and investigate the mechanism of immune tolerance. Non-obese diabetic mice fed microgram quantities of the CTB-3p531 fusion protein showed a prominent reduction in pancreatic islet inflammation and a delay in the development of diabetes. Increased anti-GAD65 IgG1, serum IgA and unchanged IgG2a antibodies titers; together with an increase of IL-4, IL-10 production and a decrease of IFN-gamma production suggested possible activation of GAD65-specific Th2 immune responses. Adoptive transfer of splenocytes indicated oral administration of CTB-3p531 fusion protein generated potent regulatory cells that can suppress diabetogenic T cells. This study demonstrates the CTB-3p531 fusion protein protects against autoimmune diabetes by generation of regulatory T cells and induction of immunological tolerance.
Gong
Zhaohui
Z
Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo 315211, China. zhaohui@ncri.org.cn
Pan
Lin
L
Le
Yanping
Y
Liu
Qiong
Q
Zhou
Mi
M
Xing
Wenhua
W
Zhuo
Renjie
R
Wang
Shaomin
S
Guo
Junming
J
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007108:Immune Tolerance; D056724:Immunity, Humoral; D056747:Immunomodulation; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D001324:Autoantigens; D011993:Recombinant Fusion Proteins; D002772:Cholera Toxin; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2