Biochemical and Biophysical Research Communications

2001

DOI: 10.1006/bbrc.2001.6100

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Intravenous Delivery of Naked Plasmid DNA for in Vivo Cytokine Expression

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Jun‐ichi Miyazaki

³

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Preparation and Injection Of Il-2 Plasmid Dna2

Il-2 In Vivo Activities and Antitumor Efficacy1

Neutralizing Anti-murine Il-2 Mab (S4b6) Enhances the In Viv1

Discussion1

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2003

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Cited by 68 publications

(48 citation statements)

References 26 publications

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“…The CD122 dependency in IL-2-depleted IL-15 KO mice led us to hypothesize that a novel CD122-targeted cytokine mediates the increased division of the memory CD8 ϩ T cells (14). To clone this factor, we developed an in vivo screening system using a hydrodynamic plasmid DNA delivery method (15). In the course of developing this assay, however, we noticed that the anti-IL-2 mAb S4B6 unexpectedly seemed to enhance the biological activities of IL-2 in vivo.…”

Section: Il-2 In Vivo Activities and Antitumor Efficacymentioning

confidence: 99%

“…The mIL-2 cDNA in the presence or absence of IL-2 tagged with 6ϫ His at the C terminus (IL-2-His) was cloned into expression vectors: the pCAGGS vector (15); and Gateway pcDNA series destination vectors (Invitrogen). The controls were the Gateway vectors containing GFP or the pCAGGS vector without insert DNA.…”

Section: Preparation and Injection Of Il-2 Plasmid Dnamentioning

confidence: 99%

“…For IL-2 protein expression in vivo, mice were given a bolus injection of 2 ml of lactate Ringer's solution containing the IL-2 plasmid DNA. The pCAGGS plasmid vector induces very strong protein expression through a combination of the CMV enhancer and chicken ␤-actin promoter (15). In this study, this vector was used only for the serum IL-2 Western blot assay, because IL-2 from the pCAGGS vector, even when as little as 10 g were given, was associated with mortality 4 -5 days after the treatment, but up to 50 g of pcDNA/mIL-2 did not have this effect.…”

Section: Preparation and Injection Of Il-2 Plasmid Dnamentioning

confidence: 99%

“…To further investigate the in vivo roles of IL-2 and IL-15 and to screen for a putative novel CD122-targeted cytokine (14), we used an in vivo hydrodynamic delivery system for plasmid DNA, by which proteins of interest can be transiently expressed and their functions examined (15,26). In the course of this assay, however, we unexpectedly found that the anti-IL-2 mAb potentiates the in vivo effects of IL-2.…”

Section: Neutralizing Anti-murine Il-2 Mab (S4b6) Enhances the In Vivmentioning

confidence: 99%

See 3 more Smart Citations

IL-2 In Vivo Activities and Antitumor Efficacy Enhanced by an Anti-IL-2 mAb

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,

²

,

³

et al. 2006

The Journal of Immunology

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IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8+ T and NK1.1high cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44highCD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.

“…The CD122 dependency in IL-2-depleted IL-15 KO mice led us to hypothesize that a novel CD122-targeted cytokine mediates the increased division of the memory CD8 ϩ T cells (14). To clone this factor, we developed an in vivo screening system using a hydrodynamic plasmid DNA delivery method (15). In the course of developing this assay, however, we noticed that the anti-IL-2 mAb S4B6 unexpectedly seemed to enhance the biological activities of IL-2 in vivo.…”

Section: Il-2 In Vivo Activities and Antitumor Efficacymentioning

confidence: 99%

“…The mIL-2 cDNA in the presence or absence of IL-2 tagged with 6ϫ His at the C terminus (IL-2-His) was cloned into expression vectors: the pCAGGS vector (15); and Gateway pcDNA series destination vectors (Invitrogen). The controls were the Gateway vectors containing GFP or the pCAGGS vector without insert DNA.…”

Section: Preparation and Injection Of Il-2 Plasmid Dnamentioning

confidence: 99%

“…For IL-2 protein expression in vivo, mice were given a bolus injection of 2 ml of lactate Ringer's solution containing the IL-2 plasmid DNA. The pCAGGS plasmid vector induces very strong protein expression through a combination of the CMV enhancer and chicken ␤-actin promoter (15). In this study, this vector was used only for the serum IL-2 Western blot assay, because IL-2 from the pCAGGS vector, even when as little as 10 g were given, was associated with mortality 4 -5 days after the treatment, but up to 50 g of pcDNA/mIL-2 did not have this effect.…”

Section: Preparation and Injection Of Il-2 Plasmid Dnamentioning

confidence: 99%

“…To further investigate the in vivo roles of IL-2 and IL-15 and to screen for a putative novel CD122-targeted cytokine (14), we used an in vivo hydrodynamic delivery system for plasmid DNA, by which proteins of interest can be transiently expressed and their functions examined (15,26). In the course of this assay, however, we unexpectedly found that the anti-IL-2 mAb potentiates the in vivo effects of IL-2.…”

Section: Neutralizing Anti-murine Il-2 Mab (S4b6) Enhances the In Vivmentioning

confidence: 99%

See 2 more Smart Citations

IL-2 In Vivo Activities and Antitumor Efficacy Enhanced by an Anti-IL-2 mAb

¹

,

²

,

³

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8+ T and NK1.1high cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44highCD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.

“…Hydrodynamics-based procedure can mediate naked DNA transfer to the liver most efficiently. It has been used in the study of transfer and expression of various genes, such as FIX [20] , IL-10 [21] , LDL [22] , HDV [23] , hepatocyte growth factor [24] , etc. The method was proved to be very efficient for delivery of these genes into the mouse liver.…”

Section: Discussionmentioning

confidence: 99%

Insulin expression in livers of diabetic mice mediated by hydrodynamics-based administration

He¹,

Ding²,

Wu³

et al. 2004

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AIM:Transfer and expression of insulin gene in vivo are an alternative strategy to improve glycemic control in type 1 diabetes. Hydrodynamics-based procedure has been proved to be very efficient to transfer naked DNA to mouse livers. The basal hepatic insulin production mediated by this rapid tail vein injection was studied to determine its effect on the resumption of glycemic control in type 1 diabetic mice. METHODS:Engineered insulin cDNA was inserted into plasmid vectors under a CMV promoter, and transferred into STZ induced diabetic mice by hydrodynamic procedure. Glucose levels, body weight of treated mice, insulin levels, immunohistology of the liver, and quantity of insulin mRNA in the liver were assayed to identify the improvement of hyperglycemic complication after plasmid administration. Sleeping Beauty, a transposon system, was also used to prolong the insulin expression in the liver. RESULTS:After plasmid administration, Plasma insulin was significantly increased in the diabetic mice and the livers were insulin-positive by immunostaining. At the same time the hyperglycemic complication was improved. The blood glucose levels of mice were reduced to normal. Glucose tolerance of the treated diabetic mice was improved. Body weight loss was also ameliorated. The rapid tail vein injection did not cause any fatal result. CONCLUSION:Our results suggested that insulin gene could be efficiently transferred into the livers of diabetic mice via rapid tail vein injection and it resulted in high level of insulin expression. The basal hepatic insulin production mediated by hydrodynamics-based administration improved the glycemic control in type 1 diabetes dramatically and ameliorated diabetic syndromes. Hydrodynamics-based administration offers a simple and efficient way in the study of gene therapy for type 1 diabetes.

Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis

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et al. 2021

Eur J Immunol

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Acumulation of oxidized membrane lipids ultimately results in ferroptotic cell death, which can be prevented by the selenoenzyme glutathione peroxidase 4 (Gpx4). In vivo conditions promoting ferroptosis and susceptible cell types are still poorly defined. In this study, we analyzed the conditional deletion of Gpx4 in mice specifically in the myeloid cell lineages. Surprisingly, development and maintenance of LysM + macrophages and neutrophils, as well as CD11c + monocyte-derived macrophages and dendritic cells were unaffected in the absence of Gpx4. Gpx4-deficient macrophages mounted an unaltered proinflammatory cytokine response including IL-1β production following stimulation with TLR ligands and activation of several inflammasomes. Accordingly, Gpx4 fl/fl LysM-cre mice were protected from bacterial and protozoan infections. Despite having the capacity to differentiate to alternatively activated macrophages (AAM), these cells lacking Gpx4 triggered ferroptosis both in vitro and in vivo following IL-4 overexpression and nematode infection. Exposure to nitric oxide restored viability of Gpx4-deficient AAM, while inhibition of iNOS in proinflammatory macrophages had no effect. These data together suggest that activation cues of tissue macrophages determine sensitivity to lipid peroxidation and ferroptotic cell death.

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