An HLA-transgenic mouse model of type 1 diabetes that incorporates the reduced but not abolished thymic insulin expression seen in patients

Jeffrey Babad, Riyasat Ali, Jennifer Schloss, Teresa P. DiLorenzo

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1 Citation (Scopus)

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Multiple genetic loci contribute to disease susceptibility in humans, with the most responsible locus being the major histocompatibility complex (MHC). Certain MHC alleles are predisposing, including the common HLA-A02:01. After the MHC, the locus conferring the strongest susceptibility to T1D is the regulatory region of the insulin gene, and alleles associated with reduced thymic insulin expression are predisposing. Mice express two insulin genes, Ins1 and Ins2. While both are expressed in beta cells, only Ins2 is expressed in the thymus. We have developed an HLA-A02:01-transgenic NOD-based T1D model that is heterozygous for a functional Ins2 gene. These mice exhibit reduced thymic insulin expression and accelerated disease in both genders. Immune cell populations are not grossly altered, and the mice exhibit typical signs of islet autoimmunity, including CD8 T cell responses to beta cell peptides also targeted in HLA-A02:01-positive type 1 diabetes patients. This model should find utility as a tool to uncover the mechanisms underlying the association between reduced thymic insulin expression and T1D in humans and aid in preclinical studies to evaluate insulin-targeted immunotherapies for the disease.

Original languageEnglish (US)
Article number7959060
JournalJournal of Diabetes Research
Volume2016
DOIs
StatePublished - 2016

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Type 1 Diabetes Mellitus
Transgenic Mice
Insulin
Major Histocompatibility Complex
varespladib methyl
Islets of Langerhans
Alleles
Genes
T-Lymphocytes
Genetic Loci
Nucleic Acid Regulatory Sequences
Disease Susceptibility
Insulin-Secreting Cells
Autoimmunity
Immunotherapy
Thymus Gland
Autoimmune Diseases
Peptides
Population

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

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title = "An HLA-transgenic mouse model of type 1 diabetes that incorporates the reduced but not abolished thymic insulin expression seen in patients",
abstract = "Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Multiple genetic loci contribute to disease susceptibility in humans, with the most responsible locus being the major histocompatibility complex (MHC). Certain MHC alleles are predisposing, including the common HLA-A∗02:01. After the MHC, the locus conferring the strongest susceptibility to T1D is the regulatory region of the insulin gene, and alleles associated with reduced thymic insulin expression are predisposing. Mice express two insulin genes, Ins1 and Ins2. While both are expressed in beta cells, only Ins2 is expressed in the thymus. We have developed an HLA-A∗02:01-transgenic NOD-based T1D model that is heterozygous for a functional Ins2 gene. These mice exhibit reduced thymic insulin expression and accelerated disease in both genders. Immune cell populations are not grossly altered, and the mice exhibit typical signs of islet autoimmunity, including CD8 T cell responses to beta cell peptides also targeted in HLA-A∗02:01-positive type 1 diabetes patients. This model should find utility as a tool to uncover the mechanisms underlying the association between reduced thymic insulin expression and T1D in humans and aid in preclinical studies to evaluate insulin-targeted immunotherapies for the disease.",
author = "Jeffrey Babad and Riyasat Ali and Jennifer Schloss and DiLorenzo, {Teresa P.}",
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AU - Babad, Jeffrey

AU - Ali, Riyasat

AU - Schloss, Jennifer

AU - DiLorenzo, Teresa P.

PY - 2016

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