Preservation of beta-cell function during immune-mediated, B7-1-dependent alpha-cell destruction.
Type 1 diabetes (T1D) is an autoimmune disease in which the pancreatic beta-cells are destroyed in an immune-mediated process. In one mouse model of T1D, the co-expression of the costimulatory molecule, B7-1, and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha, on the beta-cells leads to massive insulitis and loss of beta-cells, resulting in T1D. Here, we have investigated whether the specific loss of beta-cells is due to an intrinsic defect in the beta-cells or is a direct consequence of B7-1 expression. We show that transgenic mice expressing TNF-alpha on the beta-cells and B7-1 on the alpha-cells are resistant to the development of diabetes despite B7-1-dependent loss of alpha-cells and a massive islet inflammation consisting of T cells, B cells, macrophages and dendritic cells. Furthermore, islets with alpha-cell expression of B7-1 develop alpha-cell destruction and heavy infiltration, but maintain functional beta-cells when they are engrafted into diabetic mice that co-express TNF-alpha and B7-1 on the beta-cells. Thus, our results show that the beta-cells are able to survive in a severely inflamed organ where the neighboring alpha-cells are destroyed, suggesting that in this model B7-1 expression on the target cells is the primary determinant for the loss of islet cells.
Skak
Kresten
K
Department of Diabetes Autoimmunity, Hagedorn Research Institute, Gentofte, Denmark.
Haase
Claus
C
Michelsen
Birgitte K
BK
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000276:immunology*; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005934:Glucagon / Q000276:immunology; D052216:Glucagon-Like Peptide 1; D007150:Immunohistochemistry; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011498:Protein Precursors / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D018122:B7-1 Antigen; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha; D052216:Glucagon-Like Peptide 1; D005934:Glucagon