title: Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.
abstract: A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of autoimmune diabetes. This study was intended to find ways to prevent the development of NOD diabetes using a neutralizing anti-interleukin (IL)-12 antibody (C17.8) that inhibits Thl cell differentiation. When C17.8 was administered from 5 to 30 weeks of age, NOD mice exhibited suppression of both insulitis and diabetes. However, when C17.8 administration ceased at 15 weeks of age, 8 of 13 recipients showed diabetes at 30 weeks of age. These results suggest that IL-12 plays an important role not only in the development of effector cells but also in their activation. In contrast, when C17.8 was injected into 2-week-old female NOD mice for 6 consecutive days, all 16 recipients showed diabetes at 30 weeks of age, whereas 12 of 20 control mice became diabetic. This result suggests that depletion of endogenous IL-12 at a young age results in the enhancement of diabetes. Flow cytometric analysis indicated that activated memory T-cells were present in higher numbers after C17.8 treatment. Transfer of spleen cells from 15-week-old C17.8-treated NOD mice to NOD-scid mice resulted in an earlier onset and a higher incidence of diabetes. Furthermore, administration of C17.8 to 2-week-old NOD mice also resulted in a much earlier onset of diabetes. These results suggest that short-term treatment with anti-IL-12 antibody prohibits IL-2 production at a young age, which may influence the expansion and apoptosis of pathogenic T-cells, resulting in the acceleration of autoimmune diabetes.
authors: Department of Geriatric Medicine, Kobe University School of Medicine, Japan.
authors: K
authors: K
authors: Fujihira
authors: M
authors: M
authors: Nagata
authors: H
authors: H
authors: Moriyama
authors: H
authors: H
authors: Yasuda
authors: K
authors: K
authors: Arisawa
authors: M
authors: M
authors: Nakayama
authors: S
authors: S
authors: Maeda
authors: M
authors: M
authors: Kasuga
authors: K
authors: K
authors: Okumura
authors: H
authors: H
authors: Yagita
authors: K
authors: K
authors: Yokono
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D017690:Cell Transplantation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005260:Female; D006824:Hybridization, Genetic; D018664:Interleukin-12 / Q000276:immunology*; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD / Q000502:physiology*; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D018664:Interleukin-12