Abstract
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-γ 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.
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