Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1.

Abstract

The role of tumor necrosis factor a (TNF-a) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-a were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-a. Treatment with TNF-a caused'a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-a. Moreover, TNF-a was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-a were shared by interleukin la in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.Nonobese diabetic (NOD) mice spontaneously develop diabetes remarkably similar to human autoimmune insulindependent diabetes mellitus. There is increasing evidence that the human and the NOD disease result from immune destruction of the insulin-producing beta cells in the islets of Langerhans (1). The disease is characterized by progressive lymphocyte infiltration into the islets (insulitis) prior to the expression of overt diabetes and by the appearance of anti-islet cell antibodies in the serum (2). A T-cell-mediated autoimmune pathogenesis is implicated because the disease can be passively transferred with lymphocytes into irradiated prediabetic mice (3) and prevented by treatment with antibodies directed against Thy-1.2 (4) and L3T4 (5) or by treatment with cyclosporin A (6). Diabetes can also be prevented by treatment with antibodies to class II Ia antigens (7). Untreated animals develop profound glucose intolerance and ketosis and die within weeks of the onset of overt diabetes. The role of lymphokines, especially interferon y (IFN-y), interleukin 1 (IL-1), and tumor necrosis factor a (TNF-a), in the pathogenesis of autoimmune diabetes has received increasing attention recently (8, 9). It was shown that IFN--y and TNF-a can induce the aberrant expression of class II major histocompatibility complex (MHC) molecules on pancreatic beta cells in vitro, suggesting a role for these lymphokines in the induction of the autoimmune process in diabetes (9). A different group of investigators has suggested that IL-1 is toxic to pancreatic beta cells in vitro and that TNF-a significantly enhances this toxicity (8). Recently we have suggested that TNF-a may play a significant role in preventing autoimmune nephritis in the (NZB3 x NZW)F1 lupus nephritis model system (10). Here we present evidence that TNF-a has a major effect in vivo by protecting NOD mice from developing autoimmune insulitis and diabetes. MATERIALS AND METHODSRecombinant murine TNF-a (0.53 mg/ml; 2.6 x 107 units/ml) was kindly provided by Genentech. Recom...

IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice

“…Our present results are consistent with our earlier experience with IL-1Ra in a chemically induced IDDM model [8]. In contrast, Jacob et al found that systemic administration of tumour necrosis factor-alpha (TNF-a) and IL-1 protects NOD mice from developing insulitis [4]. However, studies in which cytokines are systemically administered may not be optimal for demonstration of their role in organspecific disorders like IDDM.…”

“…In the inbred NOD mouse, a commonly used experimental model for IDDM, allogeneic transplanted pancreatic islets are reported to be rapidly destroyed by disease recurrence in contrast to allogeneic transplanted pituitary glands [2]. Several molecular/cellular mechanisms for this graft damage have been suggested, including involvement of the proinflammatory cytokines IL-1 and interferon-gamma (IFN-g) [4][5][6]. In the present study, the role of IL-1 in this process was investigated by using an IL-1 receptor antagonist (IL-1Ra) as a potential inhibitor of the diabetogenic process, after syngeneic pancreatic transplantation, in NOD mice.…”

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

“…In particular, the expansion of antigen-experienced T cells was prolonged in TNF À/À mice and, in contrast to wtTNF mice, EAE was readily induced by a second administration of myelin oligodendrocyte glycoprotein peptide [25]. In a spontaneous mouse model of insulin-dependent diabetes mellitus, the NOD mouse, TNF led to increased [26,27] or attenuated [28][29][30] islet infiltration, depending on timing and duration of exposure of the immune system to TNF [11]. Indications for an immunoregulatory role for TNF have been also reported in mouse models of infectious diseases, such as in schistosome [31] and M. tuberculosis/BCG infections [32], where TNF was found to be required to limit immunopathologies in the liver and lung, respectively.…”

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

“…However, the role of TNF-α in Type 1 diabetes is still controversial. Previous studies in animal models for Type 1 diabetes have clearly demonstrated that TNF-α could participate in the development of diabetes, while other studies have highlighted the role of TNF-α in silencing the autoimmune process, suggesting a dual role of TNF-α in the development of the disease based on the timing of TNF-α expression [47,48,49,50,51,52,53].…”