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11.
Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes 总被引:3,自引:1,他引:3
Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347- bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596- bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35- , 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins. 相似文献
12.
M W Lightowlers M D Rickard R D Honey 《The American journal of tropical medicine and hygiene》1986,35(4):818-823
Production of specific serum antibodies following immunization with hydatid cyst fluid antigens was investigated in sheep with Echinococcus granulosus infection and in noninfected controls. Six of 10 infected animals responded to intramuscular injection of antigen by rapid production of antibodies detected in indirect hemagglutination assays. Similar responses did not occur in any of 10 noninfected controls. It is suggested that differences in the rate of response to immunization with cyst fluid antigens between groups of sheep could be exploited in serodiagnosis of E. granulosus infection in sheep. The results also suggest that low levels of antibody found in the serum of sheep infected with E. granulosus are not the result of immunosuppression or immunological tolerance, but are due to sequestration of antigen from the immune system of the host. 相似文献
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Antibody isotype and epitope specificities were examined in sheep immunized with EG95, a protective recombinant vaccine against hydatid disease. All sheep immunized with EG95 as a fusion protein with glutathione S-transferase (GST) produced prominent IgG antibodies against the EG95 portion of the protein. Linear, antibody-binding epitope specificities of EG95 were mapped using a series of 25 overlapping synthetic peptides. Three immunodominant regions were identified which generated specific IgG1 and IgG2 antibodies in the majority of vaccinated sheep. These regions corresponded to the EG95-derived sequences SLKAVNPSDPLVYKRQTAKF, DIETPRAGKKESTVMTSGSA and SALTSAIAGFVFSC. An additional immunogenic region was identified which induced almost exclusively IgG2 antibody. This epitope was located within the sequence TETPLRKHFNLTPV. The anti-parasitic, protective effects of the EG95 vaccine correlated with the detection of specific antibody to two or more of the four linear immunogenic regions. The identification of these immunogenic peptides of EG95 maybe useful in the development of a synthetic peptide vaccine as a derivative of the EG95 recombinant. 相似文献
16.
The effects of recombinant-DNA-derived interferons on the growth of myeloid progenitor cells 总被引:5,自引:0,他引:5
Interferons (IFNs) have been shown to have significant effects on hematopoietic cell growth. Previous studies defining these effects have utilized mouse and human alpha-, beta-, and gamma-IFN isolated from supernatants of stimulated cells. Despite purification, the possible presence of other lymphokines and soluble factors remains a concern. In this study, the effects of gene-cloned alpha- and gamma-IFN on colony- forming units of granulocyte/macrophage (CFU-GM) progenitors cultured from the peripheral blood of normal volunteers were examined. In addition, blast cell colonies from one patient with acute myelogenous leukemia (AML) were studied. The growth of normal CFU-GM and AML blast cell colonies was inhibited in a dose-dependent manner by gamma- and alpha-IFN. gamma-IFN was ten to 100 times more potent than alpha-IFN in that this species of IFN reduced colony formation by greater than 50% at concentrations of less than 15 antiviral U/mL. The effects of gamma- IFN were neutralized by a monoclonal antibody specific for gamma-IFN. These in vitro studies indicate that human gamma-IFN may be an important modulator of myelopoiesis. Although these data indicate a possible efficacy of gamma-IFN in the treatment of AML, the in vitro results should be considered for their in vivo significance. 相似文献
17.
目的数值模拟抗血管生成因子Angiostatin和Endostatin对肿瘤血管生成的影响。方法建立肿瘤内外血管生成的二维离散数学模型。模型耦合两种抗血管生成因子Angiostatin和Endostatin的抑制效应,数值模拟在促血管生成因子诱导下肿瘤微血管网生成,讨论血管生成抑制因子的影响。结果抗血管生成因子Angiostatin对肿瘤内外血管网络生成的速度和成熟度有抑制作用。抗血管生成因子Angiostatin和Endostatin耦合作用时,在肿瘤血管生成的早期有明显的抑制效应;在肿瘤血管生成的中后期,它们可以降低肿瘤血管化程度。结论本文模型能够较好的模拟抗血管生成因子Angiostatin和Endostatin对内皮细胞迁移和增殖的抑制作用。 相似文献
18.
Protection against hydatid disease induced with the EG95 vaccine is associated with conformational epitopes 总被引:3,自引:0,他引:3
This paper describes attempts to map the location of host-protective epitopes of a recombinant vaccine antigen by assessing the ability of truncated regions of the antigen to elicit protective immune responses in sheep. Sheep were immunised with three truncated regions (EG95-1, EG95-2 and EG95-3) of the hydatid vaccine antigen, EG95. These regions overlapped each other and corresponded to amino acids 1-70 (EG95-1), 51-106 (EG95-2) and 89-153 (EG95-3) of the full length recombinant protein. Each region elicited antibody which reacted with the parent antigen, although these reactivities were a small proportion of the level of reactivity generated by immunisation with the full length antigen. Antisera raised against each of the truncated proteins reacted with the native parasite antigen. In vaccination and parasite challenge trials in sheep, none of the truncated regions elicited significant protection against challenge infection or antibody which was lethal to the parasite in vitro. Antibodies from sheep immunised with the combination of all three overlapping truncations elicited a comparatively low but significant level of lysis of the parasite in vitro. These antigens did not inhibit anti-EG95 antibody reactivity with EG95 nor did they inhibit in vitro oncosphere killing induced by anti-EG95 antibodies. These results indicate that the major part of the immune response induced by EG95 vaccination is directed against conformational epitopes and that the host-protective epitope(s) is/are conformational. 相似文献
19.
A DNA endonuclease, isolated from the nuclei of normal human and xeroderma
pigmentosum complementation group A (XPA) cells, which recognizes
predominately pyrimidine dimers, was examined for the mechanism by which it
locates sites of damage on UVC-irradiated DNA. In reaction mixtures with
low ionic strengths (i.e. lacking KCl), the normal and XPA endonuclease
locate sites of UV damage on both naked and reconstituted nucleosomal DNA
by different mechanisms. On both of these substrates, the normal
endonuclease acts by a processive mechanism, meaning that it binds
non-specifically to DNA and scans the DNA for sites of damage, whereas the
XPA endonuclease acts by a distributive one, meaning that it randomly
locates sites of damage on DNA. However, while both the normal and XPA
endonucleases can incise UVC irradiated naked DNA, they differ in ability
to incise damaged nucleosomal DNA. The normal endonuclease showed increased
activity on UVC treated nucleosomal DNA compared with naked DNA, whereas
the XPA endonuclease showed decreased activity on the damaged nucleosomal
substrate. Since a processive mechanism of action is sensitive to the ionic
strength of the micro-environment, the KCl concentration of the reaction
was increased. At 70 mM KCI, the normal endonuclease switched to a
distributive mechanism of action and its ability to incise damaged
nucleosomal DNA also decreased. These studies show that there is a
correlation between the ability of these endonucleases to act by a
processive mechanism and their ability to incise damaged nucleosomal DNA;
the normal endonuclease, which acts processively, can incise damaged
nucleosomal DNA, whereas the XPA endonuclease, which acts distributively,
is defective in ability to incise this substrate.
相似文献
20.
Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is
associated with an increased risk of hepatocellular carcinoma (HCC). The
hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular
DNA. To determine whether nutritional factors and hormonal status may
influence the binding of AFB1 to hepatic DNA, a cross- sectional study was
performed on a total of 42 male asymptomatic hepatitis B surface antigen
(HBsAg) carriers and 43 male non-carriers in a cohort study on the
multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo,
AFB1-N7-guanine, was measured by high- performance liquid chromatography in
urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg
carriers had a higher detection rate of urinary AFB1-DNA adducts than
non-carriers and the difference was statistically significant after
multivariate adjustment. After taking into account the total AFB1 urinary
metabolite level, chronic HBsAg carrier status, and other potential
confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and
beta-carotene were positively associated with the detection rate of the
AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level
was inversely related to the presence of the adducts in urine. The
association of urinary AFB1-DNA adducts with the plasma levels of
cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was
observed at both low and high exposure levels of AFB1. There was a
synergistic interaction of plasma alpha-tocopherol with alpha- and beta-
carotene on the adduct levels. No association with the adducts was found
for plasma levels of retinol and testosterone. This study demonstrated
different associations of antioxidant vitamins with AFB1- DNA adduct
formation. The data consistent with our previous finding in cultured
woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced
AFB1-DNA adduct formation suggest that prospective investigation of the
relationship between plasma micronutrients and risk of AFB1-related HCC is
warranted.
相似文献