Transgenic expression of murine chemokine decoy receptor D6 by islets reveals the role of inflammatory CC chemokines in the development of autoimmune diabetes in NOD mice

• Published in: Diabetologia Vol. 54; no. 7; pp. 1777 - 1787
• Main Authors: Lin, G.-J., Huang, S.-H., Chen, Y.-W., Hueng, D.-Y., Chia, W.-T., Chien, M.-W., Yen, B. L., Sytwu, H.-K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-07-2011; Springer; Springer Nature B.V
• Subjects: Animals; Antigens; Autoimmune diseases; B-Lymphocytes - immunology; Biological and medical sciences; Blotting, Western; Chemokine Receptor D6; Chemokines; Chemokines, CC - genetics; Chemokines, CC - metabolism; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Flow Cytometry; Hospitals; Human Physiology; Insulin; Internal Medicine; Lymphatic system; Lymphocytes; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred NOD; Pancreas; Pathogenesis; Receptors, CCR10 - genetics; Receptors, CCR10 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Surgery; T-Lymphocytes - immunology; China; Taiwan; Chemokine; D6; NOD mice; Type 1 diabetes; Endocrinopathy; Autoimmunity; Immunopathology; Rodentia; Transgenic animal; Autoimmune disease; Chemokine receptor; Vertebrata; Mammalia; Mouse; Development
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2166-9

Aims/hypothesis
Autoimmune diabetes results from a progressive destruction of insulin-producing beta cells in the pancreatic islets by chemokine-attracted lymphocytes. Because islet cells in NOD mice produce chemokines during the development of autoimmune diabetes, we investigated the role of inflammatory CC chemokines in disease progression in these mice.
Methods
We generated a transgenic NOD mouse model that overproduces the inflammatory CC chemokine decoy receptor D6 in pancreatic islets.
Results
The frequency of diabetes and insulitis scores of transgenic mice were decreased significantly, compared with non-transgenic control littermates. Transgenic expression of
D6
(also known as
Ccbp2
) did not affect systemic lymphocyte development or alter: (1) the T cell subsets such as T helper (Th)1, Th2 and T regulatory cells; or (2) antigen-presenting cells such as dendritic cells or macrophages. The percentages and numbers of T and B lymphocytes were decreased significantly in the pancreas. Activation status, autoantigen-specific proliferation and diabetogenicity of lymphocytes were also markedly reduced.
Conclusions/interpretation
Inflammatory CC chemokines play a critical role in the development of autoimmune diabetes. Transgenic expression of
D6
in pancreatic islets of NOD mice reduced this pathogenic process by suppressing activation of autoreactive lymphocytes and by reducing migration of lymphocytes to the pancreas.