Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes

摘要

In type 1 diabetes (T1D) an intense inflammatory response destroysβcells in the pancreas, where insulin is produced and released. A therapy for T1D that reduces the specific autoimmune response in this disease while leaving the remainder of the immune system intact has long been sought. Proinsulin is a major target of adaptive immunity in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserveβcell function in T1D patients through reduction of insulin-specific T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide served as an exploratory measure of efficacy and safety. Islet-specific CD8+ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides containing pancreatic or unrelated antigens. No serious adverse events related to BHT-3021 occurred. C-peptide levels improved relative to placebo at all doses, most notably at 1 mg at 15 weeks (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8+ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8+ T cells reactive to proinsulin while preserving C-peptide over the course of dosing.