Reactive oxygen intermediates in autoimmune islet cell destruction of the NOD mouse induced by peritoneal exudate cells (rich in macrophages) but not T cells.
The non-obese diabetic (NOD) mouse spontaneously develops autoimmune Type 1 (insulin-dependent) diabetes mellitus. NOD mice exhibit massive infiltrates of T cells and macrophages into pancreatic islets (insulitis) prior to diabetes. The contribution of oxygen free radicals to the development of insulitis in NOD mice was examined by administration of its scavengers, such as superoxide dismutase and catalase. Bovine superoxide dismutase and catalase were each coupled to polyethylene glycol. The treatment with superoxide dismutase-polyethylene glycol reduced the number of islets with insulitis and increased the undamaged islet tissue, as compared with the control group. The treatment with catalase-polyethylene glycol showed a similar tendency which did not reach significance. Using a flow cytometric assay of the oxidation of 2', 7'-dichlorofluorescein, the content of reactive oxygen intermediates in islet cells in the culture system was measured and the effect of peritoneal exudate cells and T cells on their production examined. Peritoneal exudate cells, but not T cells, from NOD mice increased the content of reactive oxygen intermediates in islet cells of either the NOD mouse or the ILI mouse (MHC-identical to NOD); the addition of superoxide dismutase to the culture medium suppressed this increase in NOD or ILI islet cells. The present data support the concept that production of oxygen free radicals mediated by macrophages can damage islet beta cells, directly resulting in autoimmune Type 1 diabetes in NOD mice.
Horio
F
F
Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215.
Fukuda
M
M
Katoh
H
H
Petruzzelli
M
M
Yano
N
N
Rittershaus
C
C
Bonner-Weir
S
S
Hattori
M
M
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000494:pharmacology; D002417:Cattle; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016166:Free Radical Scavengers; D005609:Free Radicals / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010100:Oxygen / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D016166:Free Radical Scavengers; D005609:Free Radicals; D007375:Interleukin-1; D011994:Recombinant Proteins; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen