Journal Article

Unexpected Acceleration of Type 1 Diabetes by Transgenic Expression of B7-H1 in NOD Mouse Peri-Islet Glia

Song, Aihua, Yantha, Jason, Tsui, Hubert, Winer, Shawn, Paltser, Geoff, Dosch, H.-Michael, Wu, Ping, Ellis, James

2010

Overview

Autoimmune target tissues in type 1 diabetes include pancreatic β-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC. A B7-H1 transgene was placed under control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic and wild-type NOD mice were compared for transgene PD-1 affinities, diabetes development, insulitis, and pSC survival. Mechanistic studies included adoptive type 1 diabetes transfer, B7-H1 blockade, and T-cell autoreactivity and sublineage distribution. Transgenic and endogenous B7-H1 bound PD-1 with equal affinities. Unexpectedly, the transgene generated islet-selective CD8(+) bias with accelerated rather than suppressed diabetes progression. T-cells of diabetic transgenics transferred type 1 diabetes faster. There were no earlier pSC losses due to conceivable transgene toxicity, but transgenic pSC loss was enhanced by 8 weeks, preceded by elevated GFAP autoreactivity, with high-affinity T-cells targeting the major NOD K(d)-GFAP epitope, p253-261. FoxP3(+) regulatory T- and CD11c(+) dendritic cell pools were unaffected. In contrast with transgenic B7-H1 in NOD mouse β-cells, transgenic B7-H1 in pSC promotes rather than protects from type 1 diabetes. Here, ectopic B7-H1 enhanced the pathogenicity of effector T-cells, demonstrating that pSC can actively impact diabetes progression-likely through modification of intraislet T-cell selection. Although pSC cells emerge as a new candidate for therapeutic targets, caution is warranted with regard to the B7-H1-PD1 axis, where B7-H1 overexpression can lead to accelerated autoimmune disease.

• Publisher: American Diabetes Association
• Subject: Animals / Antigens, CD - analysis / Antigens, CD - genetics / Antigens, CD - metabolism / Autoimmune diseases / B7-1 Antigen - genetics / B7-H1 Antigen / Beta cells / Biological and medical sciences / CD11c antigen / CD8 antigen / Cells / Costimulator / Dendritic cells / Dendritic Cells - immunology / Development and progression / Diabetes / Diabetes mellitus / Diabetes Mellitus, Type 1 - genetics / Diabetes Mellitus, Type 1 - pathology / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Epitopes / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Foxp3 protein / Gene Expression / Genetic aspects / Glia / Glial fibrillary acidic protein / Glial Fibrillary Acidic Protein - genetics / Glial Fibrillary Acidic Protein - metabolism / Growth factors / Histocytochemistry / Humans / Immunology and Transplantation / Insulin / Insulin-Secreting Cells - physiology / Insulitis / Islands of Langerhans / Islets of Langerhans / Islets of Langerhans - pathology / Lymphocyte Activation / Lymphocytes T / Medical sciences / Membrane Glycoproteins - genetics / Mice / Mice, Inbred NOD / Mice, Transgenic / Nervous system / Neuroglia / Pancreas / Pathogenicity / PD-1 protein / Peptides - genetics / Physiological aspects / Promoter Regions, Genetic / Promoters / Research design / Schwann cells / Surface Plasmon Resonance / T-Lymphocytes - immunology / T-Lymphocytes - physiology / Toxicity / Transgenes / Type 1 diabetes