Dendritic cells and macrophages are the first and major producers of TNF-alpha in pancreatic islets in the nonobese diabetic mouse.
The nonobese diabetic (NOD) mouse spontaneously develops autoimmune insulin-dependent diabetes mellitus (IDDM) and serves as an animal model for human type I diabetes. TNF-alpha is known to be produced by islet-infiltrating mononuclear cells during insulitis and subsequent beta cell destruction and has been implicated in the pathogenesis of IDDM. Previously, T cells have been suggested as the main source of TNF-alpha in the islet infiltrate. However, on immunohistochemical analysis of TNF-alpha expression in islets, we are able to show that the staining pattern of TNF-alpha resembles that of dendritic cells (DC) and macrophages (Mphi) rather than T cells and that TNF-alpha is expressed in islets at the very early stages of insulitis when no T cells are detected. On double staining for TNF-alpha and cell surface markers, we can demonstrate that TNF-alpha staining clearly correlates with DC and Mphi, whereas there is a poor correlation with T cells. This feature was observed at both early and late stages of insulitis. TNF-alpha expression was also seen in NOD-SCID islets, in addition to a peri-islet infiltration consisting of DC and Mphi, indicating that T cells are not required for the early DC and Mphi infiltration and TNF-alpha expression in islets. In conclusion, our results show that DC and Mphi are the major, early source of TNF-alpha in the NOD islet infiltrate and that TNF-alpha can be expressed independently of T cells, indicating that the early DC and Mphi infiltration and expression of TNF-alpha are crucial in initiation of diabetes.
Dahlén
E
E
Pharmacia & Upjohn, Lund Research Center, Sweden.
Dawe
K
K
Ohlsson
L
L
Hedlund
G
G
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007700:Kinetics; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013194:Staining and Labeling; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha