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Sci Transl Med. 2017 Aug 9;9(402). pii: eaaf7779. doi: 10.1126/scitranslmed.aaf7779.

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.

Author information

1
Diabetes Research Group, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
2
Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London SE19RT, UK.
3
Department of Diabetes and Endocrinology, Guy's and St Thomas' Hospital National Health Service (NHS) Foundation Trust, London SE19RT, UK.
4
National Institute of Health Research Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London SE19RT, UK.
5
Clinical Research Facility, University Hospital of Wales, Cardiff CF14 4XN, UK.
6
Diabetes Research Unit Cymru, Swansea University, Swansea SA2 8PP, UK.
7
Joint Clinical Research Unit, University Hospitals Bristol Foundation Trust, Bristol BS2 8HW, UK.
8
Diabetes and Endocrinology Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle NE1 4LP, UK.
9
Diabetes and Endocrinology Department, Countess of Chester Hospital NHS Foundation Trust, Chester CH2 1UL, UK.
10
Division of Epidemiology and Biostatistics, Western Michigan University School of Medicine, MI 49008, USA.
11
Haematology Clinical Trials Unit, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
12
Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London SE19RT, UK. mark.peakman@kcl.ac.uk.
13
King's Health Partners Institute of Diabetes, Endocrinology and Obesity, London SE19RT, UK.

Abstract

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

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