We have previously shown that vesicles containing the spike glycoprotein of the vesicular stomatitis virus (VSV-G) can associate efficiently with immature, non-infectious, envelope-deficient retrovirus-like particles assembled by packaging cells to produce infectious, pseudotyped viruses in cell-free conditions in vitro. We have also previously reported that VSV-G can enhance DNA lipofection efficiency by interacting with liposomes to form fusogenic, serum-stable liposomes with enhanced transfection properties. Here, we report that VSV-G can form a complex directly with naked plasmid DNA in the absence of a lipofection reagent and can thereby enhance the transfection efficiency of the naked plasmid vector. Sucrose gradient sedimentation analysis demonstrated that VSV-G can also associate with plasmid DNA and murine leukemia virus (MLV) gag-pol particles to form ternary complexes that co-sediment with high DNA transfecting activity. The increased transfection efficiency with VSV-G was dependent on the presence of the polycation (Polybrene) in the culture medium during transfection. Enhanced transfection was abolished by a neutralizing antibody to VSV-G. These results may be useful in the study of retrovirus assembly, in the further design of hybrid DNA-based retrovirus-like vectors, and in the full in vitro, cell-free assembly of infectious virus-like particles from component parts.
The prolongation of survival of IL-10 cDNA transferred liver allografts might be due to inhibition of the early phase of alloimmune-response by over expression of IL-10, despite the expression of IL-2 and interferon-gamma.
Metastasis to the liver remains an important problem in the treatment of patients with gastrointestinal cancer. We examined the mechanism and effect on liver metastasis of in vivo interleukin -2 ( IL -2 ) gene transfer to the liver. RCN -9 cells derived from F344 rat colon adenocarcinoma were injected into syngeneic rats via the ileocecal vein to induce liver tumors. A total of 2.5Â10 9 pfu of adenovirus vector harboring the human IL -2 gene ( AdCMVhIL -2 ), or 2.5Â10 9 pfu of control vector encoding -galactosidase was administered before RCN -9 cell challenge. On day 14, mean tumor weight was 4.0 ± 2.4 g in the control group, whereas IL -2 -transduced livers had no tumors. Survival of AdCMVhIL -2 -treated rats was significantly longer than that of control rats ( P <.01 ). Flow cytometry demonstrated that the proportion of natural killer ( NK ) cells had increased among sinusoidal cells collected from IL -2 -transduced livers. These cells were highly cytotoxic to RCN -9 cells in vitro in the presence of a physiological high concentration of recombinant IL -2. Preventative effects of IL -2 transduction of the liver against liver metastasis were lost after depletion of NK cells by treatment with anti -asialo GM1 antibodies. Our results indicate that IL -2 gene transfer to the liver prevents liver metastasis by continuously providing physiological high concentrations of IL -2 in the liver, thereby activating sinusoidal NK cells. Cancer Gene Therapy ( 2002 ) 9, 655 -664 doi:10.1038/sj.cgt.7700483Keywords: interleukin -2; sinusoidal NK cell; gene therapy; adenovirus vector; liver metastasis; colon cancer T umor recurrence with liver metastasis sometimes occurs after surgical resection of primary colorectal carcinoma, despite no evidence of liver metastasis while in operation. These arise from handling of tumors or existence of micrometastasis during operation. Although localized solitary liver metastasis from colorectal carcinoma can be treated by surgical resection, multiple hepatic metastases cannot.
Fulminant hepatic failure is usually fatal without liver transplantation; however, orthotopic liver transportation is often difficult to perform due to the high risk of coagulopathy and the development of multiple organ failure. Auxiliary heterotopic partial liver transplantation (APLT), However, has the potential to provide an effective hepatic support system considering that the host liver is left in situ and the surgical procedure is less invasive. In this report, we describe the beneficial effects of performing 60% APLT on the hepatic function and survival of pigs with acute hepatic failure induced by hepatic artery ligation. The pigs were divided into a control group of nine animals (group 1) that had portal vein and hepatic artery ligation with a side-to-side portacaval shunt, and an APLT group of seven animals (group 2) that had portal vein and hepatic artery ligation with APLT. The two left lateral lobes of the donor liver were resected, reducing the liver weight to about 60%, and the graft was placed in the right subhepatic space. No deaths occurred intraoperatively. In group 1, eight pigs died of massive liver necrosis within 48 h and one died between 48 and 72 h (median survival 23 h). In group 2, two pigs died within 72 h due to preservation or anesthetic problems, but five survived for more than 3 days (median survival 13.4 days), with a significant difference between the two groups (P < 0.05). One animal was killed 30 days after APLT and excellent graft function was demonstrated by the synthesis of clotting factors, ammonia detoxification, and glucohomeostasis. Moreover, evidence of hepatic regeneration was found in the transplanted livers.(ABSTRACT TRUNCATED AT 250 WORDS)
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