Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD/Shi/Kbe mice by anti-MHC class I Kd monoclonal antibody.
The immune mechanisms directly responsible for beta-cell destruction in insulin-dependent diabetes are undefined. We studied the role of MHC class I-restricted T lymphocytes in the development of diabetes in cyclophosphamide (CY)-treated male and untreated female NOD mice (H-2Kd,Db). After administration of CY to 10-wk-old male NOD/Shi/Kbe mice, 37 of 64 (58%) phosphate-buffered saline-injected control mice and 13 of 22 (59%) anti-Kb and 12 of 27 (44%) anti-Db monoclonal antibody (MoAb)-injected mice became diabetic by 14 wk of age, whereas only 3 of 38 (8%) anti-Kd and 2 of 13 (15%) anti-Lyt-2 MoAb-injected mice did. In untreated female NOD/Shi/Kbe mice, 30 of 46 (65%) mice developed spontaneous diabetes by 30 wk of age, whereas none of 9 anti-Kd MoAb-injected mice became diabetic. Immunohistochemical studies showed that islet-infiltrating cells in CY-treated control mice were composed mainly of both L3T4+ and Lyt-2+ T lymphocytes, whereas many L3T4+ and very few Lyt-2+ lymphocytes infiltrated within the islets in anti-Kd MoAb-injected mice. Administration of anti-Lyt-2 MoAb induced the absence of Lyt-2+ T lymphocytes in the islet and spleen. However, anti-Kd MoAb did not change the number of spleen cells or the T-lymphocyte subset and response to concanavalin A. These results suggest that MHC class I Kd-restricted Lyt-2+ T lymphocytes play an important role as direct effector cells in destruction of beta-cells in NOD/Shi/Kbe mice.
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
T
T
Taki
M
M
Nagata
W
W
Ogawa
N
N
Hatamori
M
M
Hayakawa
J
J
Hari
K
K
Shii
S
S
Baba
K
K
Yokono
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003208:Concanavalin A; D003520:Cyclophosphamide / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D003208:Concanavalin A; D003520:Cyclophosphamide