Introduction & Objective: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease in which T lymphocytes infiltrate pancreatic Langerhans islets and destroy insulin-producing β-cells. Amarna has developed a viral gene delivery vector platform named SVec that based on its safety, non-immunogenicity and tolerogenic properties may be effective in inducing/restoring immune tolerance to the primary self-antigens of autoimmune diseases to thereby halt or revert autoimmune disease progression. We wanted to test the feasibility of SVec for the development of an effective tolerization therapy for T1DM.
Methods: Two SVec vectors encoding the primary self-antigens of the disease e.g. proinsulin (SVPI) and preproinsulin (SVPPI) were generated and vector particles produced in our SuperVero packaging cells. To obtain hepatic transgene expression groups of ten female non obese diabetic (NOD) mice were administered intravenously with SVPI or SVPPI particles six weeks after birth at a dose of 2.5x107 IU/kg body weight and glycemia was monitored up to 30 weeks after birth.
Results: Ninety percent of the untreated NOD mice developed hyperglycemia within this time span, whereas only forty percent of the SVPI-treated mice became hyperglycemic. SVPPI did not protect female NOD mice from developing T1DM. Histological inspection of the pancreases revealed that the tolerized NOD mice with SVPI had healthy islets and islets partially infiltrated with T lymphocytes. On the contrary, the pancreases of untreated mice or those injected with SVPPI were completely or partially infiltrated with T lymphocytes. Conclusion: The induction of immune tolerance to proinsulin in the liver stops the autoimmune destruction of pancreatic β-cells and hence disease progression in mice that were on their way to develop T1DM. SVec is therefore highly promising for inducing antigen-specific immune tolerance and thus for developing effective and safe tolerization therapies for patients with an autoimmune disease including T1DM.
P. de Haan: None.
