Immunotherapies are currently expanding to treat several autoimmune disorders with the goal to achieve antigen-specific tolerance. However, in type 1 diabetes (T1D), the success of such approaches remain elusive. Plasmid DNA (pDNA) platforms encoding critical antigens are easy to produce at low cost and offer prolonged antigen expression as well as design flexibility. Thus far, a limited fraction of diabetogenic T cells can be engaged using this platform due to the use of a single antigen produced in native form (i.e., pDNA encoding human proinsulin now in phase II clinical trial) despite ample evidence of epitope spreading and existence of neoepitopes. We previously demonstrated that a combination of major pDNA-encoded epitopes from multiple beta-cell antigens delivered in vivo significantly delay the onset of T1D, similar to proinsulin-pDNA, and is more suitable for precision therapy of T1D patients. Optimization is still needed to improve in vivo pDNA delivery and achieve long-lasting tolerance in T1D. Treatment was most effective when the encoded epitopes were targeted for secretion during an 8-week treatment. Antigen-specific CD4+ and CD8+ T cell responses were evident as late as 2 weeks after pDNA administration, indicating that it may be possible to reduce the frequency of treatment while preserving antigen presence in vivo. Although antigen expression and T cell responses were achieved by different routes of administration (intramuscular, intradermal or subcutaneous), the network of cells involved in presenting pDNA-encoded antigens likely differs and influences the outcome and amplitude of the immune response. Additionally, formulation of pDNAs into nanoparticles influences the draining of pDNA complexes to different lymphoid tissues, while having negligible effect on pDNA immunogenicity in vitro. Our work establishing optimal parameters of antigen targeting, expression duration and DNA delivery modalities will lead to better protocols to translate these DNA-based therapies into the clinic.
J. Postigo Fernandez: None.
American Diabetes Association (1-18-PDF-151 to J.P.F.)