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Sci Transl Med. 2013 Jun 26;5(191):191ra82. doi: 10.1126/scitranslmed.3006103.

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

Author information

1
Department for Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
2
Bayhill Therapeutics, Palo Alto, CA 94304, USA.
3
Foothill College, Los Altos, CA 94022, USA.
4
Barbara Davis Center for Childhood Diabetes, Aurora, CO 80045-6511, USA.
5
Division of Molecular Medicine, Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria 3052, Australia.
6
Pacific Northwest Diabetes Research Institute and University of Washington, Seattle, WA 98122, USA.
7
Diabetes Center for Research, University of North Carolina, Chapel Hill, NC 27599, USA.
8
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
9
Departments of Medicine and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
10
Tolerion Inc., 321 Dedalera Drive, Portola Valley, CA 94028, USA.
#
Contributed equally

Abstract

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.

Comment in

PMID:
23803704
PMCID:
PMC4516024
DOI:
10.1126/scitranslmed.3006103
[Indexed for MEDLINE]
Free PMC Article

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