Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence.

Oldstone, Michael B. A.

doi:10.1084/jem.171.6.2077

Cited by 84 publications

(49 citation statements)

References 38 publications

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“…Indeed, past studies revealed that NOD mice in gnotobiotic surroundings have a higher incidence of diabetes [37][38][39][40][41]. These observations, along with our current results and previous data from others, suggest that environmental stimuli, be they via active infections [20][21][22][23][24][25], immunizations [16][17][18][19], soluble antigens, or even dietary factors [42,43], allow for activation of T cells that exert a regulatory effect on the pathogenic potential of self-reactive lymphocytes. On a related note, studies among human patients have also suggested that infections early in life prevent the onset of autoimmune diabetes [44].…”

Section: Discussionsupporting

confidence: 74%

“…Mice protected from diabetes also showed the presence of a cellular infiltrate surrounding the islets but the g cells were normal. This finding is in full agreement with previous results, from others and also from us, that protection from diabetes by CFA or virus infection did not prevent the development of cellular infiltrate into the islets [16,20,21].…”

Section: Regulation Of Diabetes Transfer In Vivosupporting

confidence: 83%

“…For example in NOD mice and BB rats, stimulation with bacteria such as BCG or mycobacteria incorporated in complete Freund's adjuvant (CFA) resulted in marked suppression of diabetes [16][17][18][19]. Moreover, in the NOD model, viral infections or helminth infections also protected from diabetes [20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of autoimmune diabetes by non‐islet‐specific T cells — a role for the glucocorticoid‐induced TNF receptor

et al. 2004

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Diabetogenic BDC2.5 CD4 T cells induce diabetes when injected into NOD.scid mice. However, when co‐transferred with the OVA‐specific DO11.10 CD4 T cells, BDC2.5 T cells failed to cause diabetes. This inhibition depended upon the stimulation of DO11.10 T cells only with soluble OVA, which skewed their differentiation to a Th2‐type pattern of cytokine secretion in vivo. However, in vivo neutralization of IL‐4, IL‐10 or TGF‐β using monoclonal antibodies did not prevent the inhibition whereas treatment with an antibody against the glucocorticoid‐induced TNF receptor abrogated the protection from disease. In the protected mice, the diabetogenic T cells could be isolated from their spleens and shown to transfer diabetes when injected into new NOD.scid recipients. Thus, the inhibition took place without the physical or functional elimination of the diabetogenic T cells.

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Section: Discussionsupporting

confidence: 74%

Section: Regulation Of Diabetes Transfer In Vivosupporting

confidence: 83%

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Regulation of autoimmune diabetes by non‐islet‐specific T cells — a role for the glucocorticoid‐induced TNF receptor

et al. 2004

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“…In the BBDR rat, both KRV infection (6,7) and the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) (24) are diabetogenic. In contrast, in the NOD mouse viral (25)(26)(27), parasitic (28), and bacterial (29) infections, each of which is a strong activator of innate immunity, all prevent diabetes. Direct activation of innate immunity in NOD mice using purified TLR agonists also prevents spontaneous diabetes (30 -34).…”

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confidence: 99%

TLR Activation Synergizes with Kilham Rat Virus Infection to Induce Diabetes in BBDR Rats

Zipris¹,

Lien²,

Xie³

et al. 2005

The Journal of Immunology

116

115

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Virus infection is hypothesized to be an important environmental “trigger” of type 1 diabetes in humans. We used the BBDR rat model to investigate the relationship between viral infection and autoimmune diabetes. BBDR rats are diabetes-free in viral Ab-free housing, but the disease develops in ∼30% of BBDR rats infected with Kilham rat virus (KRV) through a process that does not involve infection of pancreatic β cells. Pretreatment with polyinosinic-polycytidylic (poly(I:C)), a ligand of TLR3, acts synergistically to induce diabetes in 100% of KRV-infected rats. The mechanisms by which KRV induces diabetes and TLR3 ligation facilitates this process are not clear. In this study, we demonstrate that activation of the innate immune system plays a crucial role in diabetes induction. We report that multiple TLR agonists synergize with KRV infection to induce diabetes in BBDR rats, as do heat-killed Escherichia coli or Staphylococcus aureus (natural TLR agonists). KRV infection increases serum IL-12 p40 in a strain-specific manner, and increases IL-12 p40, IFN-γ-inducible protein-10, and IFN-γ mRNA transcript levels, particularly in the pancreatic lymph nodes of BBDR rats. Infection with vaccinia virus or H-1 parvovirus induced less stimulation of the innate immune system and failed to induce diabetes in BBDR rats. Our results suggest that the degree to which the innate immune system is activated by TLRs is important for expression of virus-induced diabetes in genetically susceptible hosts.

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“…The most widely used animal model of autoimmune diabetes, the nonobese diabetic (NOD) 4 mouse, models the process poorly because the overwhelming majority of perturbants reduce the frequency of diabetes and often prevent it entirely (2). Among murine viruses, encephalomyocarditis virus (3), mouse hepatitis virus (4), lymphocytic choriomeningitis virus (5), and others reduce the frequency of disease (6). Only pancreatotropic Coxsackie virus has been documented to accelerate disease in these mice (7), but this murine infection is associated with a significant degree of inflammation and exocrine pancreatic necrosis (8) not characteristic of the prediabetic state in humans who develop type 1A diabetes (9,10).…”

mentioning

confidence: 99%

Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations

Zipris

Hillebrands

Welsh

et al. 2003

The Journal of Immunology

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Viruses are believed to contribute to the pathogenesis of autoimmune type 1A diabetes in humans. This pathogenic process can be modeled in the BBDR rat, which develops pancreatic insulitis and type 1A-like diabetes after infection with Kilham’s rat virus (RV). The mechanism is unknown, but does not involve infection of the pancreatic islets. We first documented that RV infection of BBDR rats induces diabetes, whereas infection with its close homologue H-1 does not. Both viruses induced similar humoral and cellular immune responses in the host, but only RV also caused a decrease in splenic CD4+CD25+ T cells in both BBDR rats and normal WF rats. Surprisingly, RV infection increased CD4+CD25+ T cells in pancreatic lymph nodes of BBDR but not WF rats. This increase appeared to be due to the accumulation of nonproliferating CD4+CD25+ T cells. The results imply that the reduction in splenic CD4+CD25+ cells observed in RV-infected animals is virus specific, whereas the increase in pancreatic lymph node CD4+CD25+ cells is both virus and rat strain specific. The data suggest that RV but not H-1 infection alters T cell regulation in BBDR rats and permits the expression of autoimmune diabetes. More generally, the results suggest a mechanism that could link an underlying genetic predisposition to environmental perturbation and transform a “regulated predisposition” into autoimmune diabetes, namely, failure to maintain regulatory CD4+CD25+ T cell function.

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Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence.

Cited by 84 publications

References 38 publications

Regulation of autoimmune diabetes by non‐islet‐specific T cells — a role for the glucocorticoid‐induced TNF receptor

Regulation of autoimmune diabetes by non‐islet‐specific T cells — a role for the glucocorticoid‐induced TNF receptor

TLR Activation Synergizes with Kilham Rat Virus Infection to Induce Diabetes in BBDR Rats

Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations

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