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Sci Rep. 2018 Sep 20;8(1):14106. doi: 10.1038/s41598-018-32546-4.

Proinsulin-mediated induction of type 1 diabetes in HLA-DR4-transgenic mice.

Author information

1
School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, Guy's Hospital, London, United Kingdom. johan.verhagen@kcl.ac.uk.
2
UCB Pharma Ltd, Slough, United Kingdom.
3
School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, King's College London, Guy's Hospital, London, United Kingdom.
4
Oncogenes and Tumour Metabolism Laboratory, The Francis Crick Institute, London, UK.
5
Institute of Diabetes, Endocrinology and Obesity, King's Health Partners, London, UK.

Abstract

Antigen-specific immunotherapy of autoimmune disease currently remains the only potentially curative approach. However, translation of promising pre-clinical results into successful clinical application has proven challenging. In part, this is because pre-clinical findings in mouse models have to be redesigned for human application due to differences in MHC II. To reduce the gap between pre-clinical and clinical studies, we have created a novel mouse model that expresses human HLA-DR4, but no endogenous MHC on antigen-presenting cells. Moreover, human B7.1 (CD80) is expressed in the pancreatic islets under the control of the rat insulin promoter. Although this model does not develop diabetes spontaneously, it is susceptible to the induction of type 1 diabetes by challenging mice with overlapping peptides derived from murine proinsulin-2 in adjuvant. Unlike the NOD model of spontaneous type 1 diabetes, but akin to the human condition, this model does not have a gender bias. Furthermore, similar to the human condition, the disease is characterised by a diverse leucocyte infiltration of the pancreatic islets and the formation of anti-proinsulin auto-antibodies. The model that we report here offers detailed insights into type-1 diabetes and is expected to prove instrumental when studying the mechanism of action in translational, antigen-specific immunotherapy.

PMID:
30237494
PMCID:
PMC6148278
DOI:
10.1038/s41598-018-32546-4
[Indexed for MEDLINE]
Free PMC Article

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