Treatment of murine lupus with cDNA encoding IFN-γR/Fc

Lawson, Brian R.; Prud’homme, Gérald J.; Chang, Ying; Gardner, Humphrey; Kuan, Jason; Kono, Dwight H.; Theofilopoulos, Argyrios N.

doi:10.1172/jci10167

Cited by 162 publications

(126 citation statements)

References 49 publications

(35 reference statements)

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“…38 In lupus mouse models, however, a more prominent role for interferon-γ rather than interferon-α has been reported. 39,40 A prominent role for interferon-γ is also seen in our mouse model as suggested by the differentially expressed gene profiles (Figure 8). In the MRL/lpr lupus-prone mouse, 24 interferon-regulated genes are differentially expressed in the spleen relative to MRL+/+ controls.…”

Section: Discussionsupporting

confidence: 58%

Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients

et al. 2008

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.

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Section: Discussionsupporting

confidence: 58%

Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients

et al. 2008

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“…84,140 Lawson and co-workers 137,141 inoculated an IFN-gR/ IgG1-Fc plasmid into MRL lpr/lpr mice and observed low-level expression compared with a previous study in NOD and CD1 mice with the same vector. However, serum IFN-g levels of untreated MRL lpr/lpr mice are very high.…”

Section: Gene Therapy With Cytokine Inhibitorsmentioning

confidence: 86%

“…141 Thus, electroporation was remarkably effective, and it is likely that this technique will be even more relevant to other species. Indeed, in primates and other large mammals i.m.…”

Section: Gene Therapy With Cytokine Inhibitorsmentioning

confidence: 99%

“…injections, especially with electroporation, protected MRL lpr/lpr mice from early death, and reduced autoantibody titres, renal disease, and histological markers of lupus-like disease. 141 Most notably, when therapy was initiated in 4-month-old diseased mice, survival was extended beyond expectations, with 100% of the mice staying alive at 14 months of age compared with none in the control group. Remarkably, disease severity was reduced or even suppressed in the treated group.…”

Section: Gene Therapy With Cytokine Inhibitorsmentioning

confidence: 99%

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Immunopathology and the gene therapy of lupus

Mageed

Prud’homme

2003

Gene Ther

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“…After DNA injection, electroporation was immediately applied to DNA injected muscles by caliper-type electrodes of ECM830 (Genetronics Inc., San Diego, CA, USA) as we have previously described. 26,50 For mbPPI in vivo expression, mbPPI transcripts were detected from DNA injected muscles by RT-PCR. Briefly, mice were killed and DNA vector-injected TA muscles were excised and homogenized.…”

Section: Confirmation Of In Vivo Transgenic Expressionmentioning

confidence: 99%