Local production of immunosuppressive cytokines will be one of the most suitable therapeutic strategies against organ-specific autoimmune diabetes. To establish such a new therapy, we constructed recombinant adenoviral vectors with inserted mIL-12p40 (Ad.IL-12p40) and mIL-10 (Ad.IL-10). Sufficient amounts of IL-12p40 and IL-10 were secreted by relevant adenovirus-transfected nonobese diabetic (NOD) islets. Shortly after transfection, 400 NOD islets transfected with Ad.IL-12p40 or Ad.IL-10 were transplanted under the renal capsule of a newly diabetic NOD mouse. NOD mice with IL-12p40-producing islet grafts kept normoglycemia in all of 14 grafted mice for over 4 wk after transplantation. In contrast, NOD mice with IL-10-producing islet grafts became diabetic in all of six grafted mice within 2 wk after transplantation. Reverse transcription-PCR analysis revealed that local production of IL-12p40 led to the decrease of interferon-␥ and the augmentation of transforming growth factor-␤ at the graft site. These results suggest that IL-12 plays an important role in the destruction of islet cells at the inflamed site of autoimmunity. Such a local blockade of IL-12 would be a useful gene therapy for human autoimmune diabetes. (

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 Th1 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.

No abstract

No abstract

All forms of tobacco cause cardiovascular disease, and tobacco-related disease is a leading cause of death worldwide. Smoking oxidizes low-density lipoprotein (LDL) particles, and oxidized LDL particles are thought to play an early and critical role in atherosclerogenesis. Hyper-low-density lipoproteinemia is one of the risk factors for cardiovascular disease, but small, dense LDL particles have been associated with an increased risk for cardiovascular disease. Small, dense LDL correlates with some cardiovascular risk factors such as diabetes mellitus, hypertriglyceridemia, hypo-high-density lipoproteinemia, and hypertension. Although smoking is also a major risk factor for cardiovascular disease, the relationship between smoking and small, dense LDL particles has not been described previously. Our cross-sectional study examined this relationship in a population of 18 healthy young adult men (9 smokers and 9 never-smokers, aged 21-24 years) from the same college. Concentrations of blood lipids and the LDL migration index (LDL-MI) were examined. Although concentrations of blood lipids did not differ between smokers and never-smokers, the LDL-MI had a strong tendency to be lower in smokers. The LDL-MI is larger in the presence of a greater proportion of small, dense LDL particles. These results indicate that tobacco smoking is associated with a decrease in the proportion of small, dense LDL particles. Regardless of these surprising results, we do not recommend smoking, given that it is a major cause of cardiovascular disease.