Prevention of Cyclophosphamide-Induced and Spontaneous Diabetes in NOD/Shi/Kbe Mice by Anti-MHC Class I Kd Monoclonal Antibody

Abstract

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.

Gamma Interferon Paradoxically Inhibits the Development of Diabetes in the NOD Mouse

“…Autoreactive MHC class I restricted CD8+ T cells are found in NOD islets [29]. Further, anti MHC class I monoclonal administration inhibits spontaneous diabetes while MHC class I deficient mice are resistant to diabetes [30,31]. Thus, the depression of MHC class I expression in spleen cells from rIFN-treated mice could in part mediate the diabetes sparing activity of rIFN-administration.…”

MHC Class I-Restricted Determinants on the Glutamic Acid Decarboxylase 65 Molecule Induce Spontaneous CTL Activity

“…The evidence to date suggests that K d -restricted, rather than D brestricted, CTL responses are involved in ␤ cell destruction (29,30). To identify potential CD8…”

Prevention of autoimmune insulitis in nonobese diabetic mice by expression of major histocompatibility complex class I Ld molecules.

“…Second, both CD4-positive and CD8-positive T cells are required for the induction of diabetes in transfer experiments (23,24), and the development of cyclophosphamide-induced diabetes can be prevented by anti-CD8 antibody (25). Similarly, the anti-H-2Kd antibody can prevent spontaneous and cyclophosphamide-induced diabetes (26). Ohashi et al (27) and Oldstone et al (28) have developed viral antigen transgenic mice in which viral infection triggers destruction of ( cells mediated by an anti-viral cytotoxic T-cell response, leading to diabetes.…”