Transferring part of an insulin gene into liver cells triggers a specific immune response that protects mice from one form of diabetes. Type 1 diabetes occurs when T cells target and kill insulin-producing islet cells in the pancreas. Maria Grazia Roncarolo of Stanford University in California and her team transferred genes to hepatocytes which protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs.
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.
Brian Feldman is one of the inventors of a microchip-based test for diagnosing type-1 diabetes. Norbert von der Groeben
SOURCES – Nature, Science Translational Medicine, Stanford University