In situ characterization of dendritic cells occurring in the islets of nonobese diabetic mice during the development of insulitis.
Type 1 diabetes mellitus in nonobese diabetic (NOD) mice, a well-known model of human type 1 diabetes, has been considered to be caused by the destruction of insulin-producing beta cells in the islets of the pancreas by self-reactive T cells. Antigen-presenting cells like dendritic cells (DCs) and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. These immunohistochemical studies revealed that CD11c-positive DCs already appeared in the islets of NOD mice as early as 4 weeks old when lymphocytes were not yet infiltrated in the islet, and thus insulitis was not developed. DCs were first observed to locate around swollen parainsular vessels. From age 7 weeks onward to age 13 weeks, more DCs were present in parainsular areas where lymphocytes had also accumulated, and the number of DCs in the islets as well as lymphocytes increased. However, at the end stage of insulitis from age approximately 17 weeks onward, the number of DCs in the islets decreased. In contrast, accumulation of DCs in the para- and periislets was not observed in 7- and 17-week-old ICR female mice that do not develop type 1 diabetes. Double-staining studies using confocal laser scanning microscopy showed that the CD11c-positive DCs coexpress both major histocompatibility (MHC) class II and costimulatory molecules, CD80 and CD86. Electron-microscopy studies further demonstrated that cell bodies and processes of the DCs make close contact with lymphocytes. These results suggest that DCs infiltrated into the pancreatic islets are capable of stimulating T cells by the MHC class II-antigenic peptide complex, together with costimulatory molecules, which eventually lead to the beta-cell destruction in NOD mice.
Shinomiya
M
M
Third Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Japan. mizuhos@m.ehime-u.ac.jp
Nadano
S
S
Shinomiya
H
H
Onji
M
M
D000818:Animals; D000911:Antibodies, Monoclonal; D018845:CD11 Antigens / Q000032:analysis; D002450:Cell Communication; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology*; D005260:Female; D007515:Islets of Langerhans / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D008854:Microscopy, Electron; D008871:Microvilli / Q000648:ultrastructure; D013601:T-Lymphocytes / Q000473:pathology
D000911:Antibodies, Monoclonal; D018845:CD11 Antigens