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Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3(+) T-regs
Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3(+) T-regs SCIENCE TRANSLATIONAL MEDICINE Akbarpour, M., Goudy, K. S., Cantore, A., Russo, F., Sanvito, F., Naldini, L., Annoni, A., Roncarolo, M. G. 2015; 7 (289)Abstract
Antigen (Ag)-specific tolerance in type 1 diabetes (T1D) in human has not been achieved yet. Targeting lentiviral vector (LV)-mediated gene expression to hepatocytes induces active tolerance toward the encoded Ag. The insulin B chain 9-23 (InsB9-23) is an immunodominant T cell epitope in nonobese diabetic (NOD) mice. To determine whether auto-Ag gene transfer to hepatocytes induces tolerance and control of T1D, NOD mice were treated with integrase-competent LVs (ICLVs) that selectively target the expression of InsB9-23 to hepatocytes. ICLV treatment induced InsB9-23-specific effector T cells but also FoxP3(+) regulatory T cells (Tregs), which halted islet immune cell infiltration, and protected from T1D. Moreover, ICLV treatment combined with a single suboptimal dose of anti-CD3 monoclonal antibody (mAb) is effective in T1D reversal. Splenocytes from LV.InsB9-23-treated mice, but not from LV.OVA (ovalbumin)-treated control mice, stopped diabetes development, demonstrating that protection is Ag-specific. Depletion of CD4(+)CD25(+)FoxP3(+) T cells led to diabetes progression, indicating that Ag-specific FoxP3(+) Tregs mediate protection. Integrase-defective LVs (IDLVs).InsB9-23, which alleviate the concerns for insertional mutagenesis and support transient transgene expression in hepatocytes, were also efficient in protecting from T1D. These data demonstrate that hepatocyte-targeted auto-Ag gene expression prevents and resolves T1D and that stable integration of the transgene is not required for this protection. Gene transfer to hepatocytes can be used to induce Ag-specific tolerance in autoimmune diseases.
View details for DOI 10.1126/scitranslmed.aaa3032
View details for Web of Science ID 000355179800004
View details for PubMedID 26019217