Diabetes and other autoimmune endocrine diseases
The induction of antigen (Ag)-specific tolerance represents a therapeutic option for Type-1 diabetes (T1D). We showed that a single administration of lentiviral vector (LV), enabling expression of insulin B chain 9-23 (InsB9-23) in hepatocytes, arrests beta-cell destruction in NOD mice at advanced pre-diabetic stage, by generating InsB9-23-specific FoxP3+ T regulatory cells (Tregs). Here we show that LV.InsB in combination with a suboptimal dose (1X 5µg) of anti-CD3 mAb (combined therapy, CT5) reverts overt diabetes, prevents recurrence of autoimmunity and maintains insulin independence when provided the day after syngeneic or allogeneic pancreatic islet transplantation in 50% and 40% of treated mice, respectively. Therefore, we investigated whether CT could be optimized (LV.InsB+anti-CD3 1X25µg, CT25) to be more efficient in arresting recurrence of autoimmunity and possibly suppress allo-response to transplanted islets. To establish the CT-driven tolerogenic program prior to islet transplantation, we transplanted allogeneic islets 7 days after CT25. Results indicate that 100% of diabetic NOD mice treated with CT25 and transplanted with Balb-c islets (at glycemia <500mg/dL) remained normoglycemic for 100 days, displayed a reduced T cell responsiveness to InsB9-23 stimulation and an increased frequency of Tregs in pancreatic infiltrates and lymph-nodes. Histological analysis showed that the transplant was lost and cured mice displayed a reduced insulitis compatible with their glycemic levels.
Overall, results indicate that optimized CT25, via induction of InsB9-23-specific FoxP3+ Tregs and control InsB9-23-specific effector T cells, represents a curative treatment for T1D when associated with allogeneic islets transplantation to restore activity of the endogenous beta-cell mass.