Kupffer Cell- Mediated Cytotoxicity Induced by Lipopolysaccharide0111:b4 Is Greater in Dogs Than in Rats and Monkeys

Hamano, Takako; Tong, Vincent; Mutai, Mamoru; Hayashi, Masao; Tanaka, Eiji

doi:10.2131/jts.27.1

Cited by 6 publications

(2 citation statements)

References 47 publications

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“…47 Canine Kupffer cells are more reactive than Kupffer cells from rat or monkey, and secrete greater levels of cytokines interleukin-1b and interleukin-6 in response to lipopolysaccharide. 48 Depletion of Kupffer cells does not negatively impact DNA delivery or gene expression after hydrodynamic delivery in mice. 38 Future experiments will determine whether a drug or combination of drugs that block Kupffer cell activity and/or prevents the release of circulating immune cells is effective at achieving a longer duration of expression.…”

Section: Discussionmentioning

confidence: 99%

Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery ofSleeping BeautyTransposons Using Balloon Catheters

et al. 2017

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The Sleeping Beauty transposon system has been extensively tested for integration of reporter and therapeutic genes in vitro and in vivo in mice. Dogs were used as a large animal model for human therapy and minimally invasive infusion of DNA solutions. DNA solutions were delivered into the entire liver or the left side of the liver using balloon catheters for temporary occlusion of venous outflow. A peak intravascular pressure between 80 and 140 mmHg supported sufficient DNA delivery in dog liver for detection of secretable reporter proteins. Secretable reporters allowed monitoring of the time course of gene products detectable in the circulation postinfusion. Canine secreted alkaline phosphatase reporter protein levels were measured in plasma, with expression detectable for up to 6 weeks, while expression of canine erythropoietin was detectable for 7-10 days. All animals exhibited a transient increase in blood transaminases that normalized within 10 days; otherwise the treated animals were clinically normal. These results demonstrate the utility of a secreted reporter protein for real-time monitoring of gene expression in the liver in a large animal model but highlight the need for improved delivery in target tissues to support integration and long-term expression of Sleeping Beauty transposons.

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Section: Discussionmentioning

confidence: 99%

Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery ofSleeping BeautyTransposons Using Balloon Catheters

et al. 2017

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“…However, in the canine macrophage cell line DH82, lipopolysaccharide treatment has been shown to induce inflammatory activation through NFκΒ (Kim et al 2006). Lipopolysaccharides induce the expression of IL-6 in canine macrophages, such as DH82 cells (Fujimoto et al 2012), blood mononuclear cells and Kupffer cells in vitro (Hamano et al 2002;Shi et al 1995). Moreover, IL-6 expression is associated with inflammation (Spitzbarth et al 2011) and macrophage infiltration into inflamed tissues in dog (Klocke et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue macrophages in non-rodent mammals: a comparative study

et al. 2015

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The stromal vascular fraction (SVF) of adipose tissue in rodents and primates contains mesenchymal stem cells and immune cells. SVF cells have complex metabolic, immune and endocrine functions with biomedical impact. However, in other mammals, the amount of data on SVF stem cells is negligible and whether the SVF hosts immune cells is unknown. In this study, we show that the SVF is rich in immune cells, with a dominance of adipose tissue macrophages (ATMs) in cattle (Bos primigenius taurus), domestic goat (Capra aegagrus hircus), domestic sheep (Ovis aries), domestic cat (Felis catus) and domestic dog (Canis familiaris). ATMs of these species are granulated lysosome-rich cells with lamellipodial protrusions and express the lysosome markers acid phosphatase 5 (ACP-5) and Mac-3/Lamp-2. Using ACP-5 and Mac-3/Lamp-2 as markers, we additionally detected ATMs in other species, such as the domestic horse (Equus ferus caballus), wild boar (Sus scrofa) and red fox (Vulpes vulpes). Feline and canine ATMs also express the murine macrophage marker F4/80 antigen. In the lean condition, the alternative macrophage activation marker CD206 is expressed by feline and canine ATMs and arginase-1 by feline ATMs. Obesity is associated with interleukin-6 and interferon gamma expression and with overt tyrosine nitration in both feline and canine ATMs. This resembles the obesity-induced phenotype switch of murine and human ATMs. Thus, we show, for the first time, that the presence of ATMs is a general trait of mammals. The interaction between the adipose cells and SVF immune cells might be evolutionarily conserved among mammals.

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Dogs Are More Sensitive to Antagonists of Inhibitor of Apoptosis Proteins Than Rats and Humans: A Translational Toxicokinetic/Toxicodynamic Analysis

Wong

Budha²,

West

et al. 2012

Toxicological Sciences

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Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-α) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFκB signaling, at lower exposures compared with rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semimechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given iv GDC-0152 doses. Estimated TD parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared with rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300-2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-α driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggest dogs are more sensitive to IAP antagonists compared with humans and rats. This study illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans.

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Kupffer Cell- Mediated Cytotoxicity Induced by Lipopolysaccharide0111:b4 Is Greater in Dogs Than in Rats and Monkeys

Cited by 6 publications

References 47 publications

Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery ofSleeping BeautyTransposons Using Balloon Catheters

Transgene Expression in Dogs After Liver-Directed Hydrodynamic Delivery ofSleeping BeautyTransposons Using Balloon Catheters

Adipose tissue macrophages in non-rodent mammals: a comparative study

Dogs Are More Sensitive to Antagonists of Inhibitor of Apoptosis Proteins Than Rats and Humans: A Translational Toxicokinetic/Toxicodynamic Analysis

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