Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma.
Interferon-gamma (IFN-gamma) is produced during the response to infection and participates in immunostimulatory events. We have previously reported the induction of diabetes in transgenic mice (ins-IFN-gamma) in which the expression of the lymphokine IFN-gamma is directed by the insulin promoter. This diabetes is a result of the progressive destruction of pancreatic islets that occurs with the influx of inflammatory cells. Here we demonstrate that this islet cell loss is mediated by lymphocytes, that engrafted histocompatible islets are destroyed, and that lymphocytes from the transgenic mice are cytotoxic to normal islets in vitro. These results indicate that the pancreatic expression of IFN-gamma can result in a loss of tolerance to normal islets, consistent with its role as an inducer of costimulatory activity, which is essential for lymphocyte activation during an immune response.
Sarvetnick
N
N
Department of Developmental Biology, Genentech, Inc., South San Francisco, California 94080.
Shizuru
J
J
Liggitt
D
D
Martin
L
L
McIntyre
B
B
Gregory
A
A
Parslow
T
T
Stewart
T
T
D000818:Animals; D000941:Antigens / Q000276:immunology; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D015870:Gene Expression; D006084:Graft Rejection; D007108:Immune Tolerance; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation; D007668:Kidney; D008099:Liver; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011169:Portal Vein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000941:Antigens; D007371:Interferon-gamma