Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8(+) T Cells in Type 1 Diabetes
| Autor: | Roep, B.O., Solvason, N., Gottlieb, P.A., Abreu, J.R.F., Harrison, L.C., Eisenbarth, G.S., Yu, L.P., Leviten, M., Hagopian, W.A., Buse, J.B., Herrath, M. von, Quan, J., King, R.S., Robinson, W.H., Utz, P.J., Garren, H., Steinman, L., BHT-3021 Investigators |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male endocrine system medicine.medical_specialty endocrine system diseases T cell Enzyme-Linked Immunosorbent Assay CD8-Positive T-Lymphocytes Biology chemistry.chemical_compound Immune system Antigen Internal medicine medicine Humans Cytotoxic T cell Proinsulin C-Peptide C-peptide Pancreatic islets General Medicine Acquired immune system Diabetes Mellitus Type 1 medicine.anatomical_structure Endocrinology chemistry Female Plasmids |
| Zdroj: | Science Translational Medicine, 5(191) |
| Popis: | In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the β cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets 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 the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific CD8⁺ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 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 was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⁺ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+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). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. 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. |
| Databáze: | OpenAIRE |
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