Interferon-β

Schwarting, Andreas; Paul, Kathrin; Tschirner, Stefan; Menke, Julia; Hansen, Torsten; Brenner, Walburgis; Kelley, Vicki Rubin; Relle, Manfred; Galle, Peter R.

doi:10.1681/asn.2004111014

Cited by 64 publications

(40 citation statements)

References 38 publications

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“…27 Urine albumin/creatinine ratios and serum dsDNA autoantibody IgG isotype titers were determined as described previously. 23 Paraffin sections (5 m) for silver and periodic acid-Schiff stains were prepared following routine protocols.…”

Section: Evaluation Of Systemic Lupusmentioning

confidence: 99%

Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Kulkarni

Pawar

Purschke

et al. 2007

Journal of the American Society of Nephrology

168

124

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The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the L-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL lpr/lpr mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36 -based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.

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Section: Evaluation Of Systemic Lupusmentioning

confidence: 99%

Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Kulkarni

Pawar

Purschke

et al. 2007

Journal of the American Society of Nephrology

168

124

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“…Deficiency of the type I IFN-R surprisingly worsened lymphoproliferation, autoantibody production and end-organ disease, thus demonstrating that type I IFN exerted a protective effect on MRL/lpr mice. 9 Initiating IFN-b treatment in MRL/lpr mice with mild and advanced disease highly effective in prolonging survival and ameliorating the clinical (renal function, proteinuria, splenomegaly and skin lesions), serologic (autoantibodies and cytokines) and histologic parameters of the lupus-like disease; 10 however, IFN-a has been demonstrated to play a role in the disease pathogenesis in MRL/lpr mice by inducing the overexpression of Fas ligand on MRL/lpr lymphocytes and on their spontaneous Fas-mediated cytotoxic potential, which could be responsible for a chronic, nonantigenspecific autoimmune attack on organs expressing low levels of Fas. 11 MRL/lpr mice, in susceptible genetic backgrounds, such as MRL, exhibit a lymphoproliferative disorder that evolves into severe systemic autoimmunity due to defective Fas-induced death.…”

Section: Introductionmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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“…3,4 More recently, IFN-␤1a was shown to attenuate lupus nephritis in MRF-Fas lpr mice. 5 This provided a reasonable, if unadventurous, justification for examining the effects of IFN-␤1a on the evolution of nephrotoxic nephritis in WKY rats, a robust model of acute inflammation and progressive renal scarring. The results were both clear-cut and surprising: IFN-␤1a had no effect on the acute glomerular inflammation, progressive renal scarring, or the development of renal failure, but despite this, proteinuria was reduced by nearly 75% even when treatment was started after the onset of disease.…”

mentioning

confidence: 99%

Interferon-β

Rees

Kain

2007

Journal of the American Society of Nephrology

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Experimental studies to test the latest cytokine (or antibodies to it) in models of glomerular injury appear on an almost industrial scale. Most show modest benefits without providing serious mechanistic insights or the confidence that they will ever become clinical therapies. The article by Satchell et al. 1 in this issue of JASN describing the effect of IFN-␤1a in models of glomerulonephritis is different for at least three reasons: (1) It identifies a potential renal use for a cytokine already commonly applied in the clinic for other diseases; (2) it documents a striking reduction in proteinuria; and (3) it includes in vitro studies with glomerular endothelial cells and podocytes that not only provide a possible explanation for the in vivo results but also raise questions about the nature of the glomerular filtration barrier.Type 1 interferons, such as IFN-␤1a, are unusual in that they have well-documented immunosuppressive and antiinflammatory properties as well as inhibitory effects on fibroblast proliferation and scarring. 2 Type 1 IFN are an established treatment for chronic relapsing multiple sclerosis and for hepatitis C infection. 3,4 More recently, IFN-␤1a was shown to attenuate lupus nephritis in MRF-Fas lpr mice. 5 This provided a reasonable, if unadventurous, justification for examining the effects of IFN-␤1a on the evolution of nephrotoxic nephritis in WKY rats, a robust model of acute inflammation and progressive renal scarring. The results were both clear-cut and surprising: IFN-␤1a had no effect on the acute glomerular inflammation, progressive renal scarring, or the development of renal failure, but despite this, proteinuria was reduced by nearly 75% even when treatment was started after the onset of disease. The specific effect of IFN-␤1a on proteinuria was confirmed in two other models: Thy1.1 nephritis, in which it was equally effective, and puromycin nephropathy, in which it was even more so and decreased proteinuria by 97%.Uniquely, these studies dissociate a marked reduction of proteinuria from all other aspects of renal injury in these or, indeed, other rodent models of glomerular injury. Although unable to test directly whether IFN-␤1a influenced glomerular permeability, Satchell et al. tested its effect on cultured human glomerular endothelial cells and conditionally immortalized a human podocyte cell line. They found that IFN␤1a increased electrical resistance across the cultures (a surrogate marker for permeability for fluids and solutes) and decreased their permeability to BSA. This in turn led them to propose that IFN-␤1a reduces proteinuria through a direct effect on the glomerular filtration barrier mediated through effects on glomerular endothelium and/or podocytes. This of course needs to be proved.These studies did not address the issue of how IFN-␤1a reduced permeability glomerular endothelium and podocytes; however, there are clues from numerous previous studies on other types of vascular endothelium, including brain and retinal microvascular endothelia, bovine aortic end...

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Interferon-β

Cited by 64 publications

References 38 publications

Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Spiegelmer Inhibition of CCL2/MCP-1 Ameliorates Lupus Nephritis in MRL-(Fas)lpr Mice

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Interferon-β

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