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InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation.
InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation. Diabetes Russo, F., Citro, A., Squeri, G., Sanvito, F., Monti, P., Gregori, S., Roncarolo, M. G., Annoni, A. 2020Abstract
The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests beta cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5g CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in 50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25g CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous beta cell mass.
View details for DOI 10.2337/db19-1249
View details for PubMedID 33122392