Tumor necrosis factor production is deficient in diabetes-prone BB rats and can be corrected by complete Freund's adjuvant: A possible immunoregulatory role of tumor necrosis factor in the prevention of diabetes

Abstract

The Bio-Breeding (BB) rat develops spontaneous insulin-dependent diabetes mellitus (IDDM) and provides a useful animal model to study this human autoimmune disease. Treatment of BB rats with tumor necrosis factor (TNF) has been reported to prevent the development of IDDM. This suggests that deficient TNF production may be involved in the immunopathogenesis of autoimmune diabetes. In this study, we evaluated TNF production in diabetes-resistant (DR) BB rats, diabetes-prone (DP) BB rats, and DP BB rats protected from diabetes by the immunoadjuvant, complete Freund's adjuvant (CFA). TNF production in short-term cultures of peritoneal macrophages from DP rats was significantly less than that from control DR rats, both in the basal state and after stimulation with either interferon-γ (IFN-γ) or lipopolysaccharide (LPS) in vivo and in vitro. In contrast, TNF production by macrophages from CFA-injected DP rats (basal and IFN-γ or LPS-stimulated) was equal to or greater than that by macrophages from DP rats and similar to TNF production by macrophages from CFA-injected DR rats. These results suggest that development of autoimmune diabetes in BB rats may be causally related to deficient macrophage production of TNF, and that upregulation of TNF production may protect against diabetes development.