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B L Davidson

Publications and source records attributed to B L Davidson.

166 records · Page 10Linked to original sources
PubMedDate not supplied

Long-term reversal of hypercholesterolemia in low density lipoprotein receptor (LDLR)-deficient mice by adenovirus-mediated LDLR gene transfer combined with CD154 blockade.

BACKGROUND: Deficiency of the low density lipoprotein receptor (LDLR) results in abnormal elevation of cholesterol within the intermediate and low density plasma lipoproteins (IDL/LDL), and predisposes to early onset atherosclerosis. Cholesterol reduction after adenovirus-mediated LDLR gene transfer to LDLR-deficient animals is transient, due to the elicitation of an immune response. METHODS: The LDLR-deficient mouse was used as a model to investigate adenovirus-mediated LDLR gene transfer combined with short-term immunosuppression as a cholesterol lowering therapy. Mice were infused with replication-deficient recombinant adenovirus encoding LDLR under control of the cytomegalovirus promoter/enhancer (AdLDLR), and injected with a blocking antibody directed against CD154 (CD40 ligand) to suppress immune responses against the vector and foreign transgene product. RESULTS: Mice given AdLDLR and treated with anti-CD154 expressed LDLR on hepatocytes and maintained cholesterol levels below or within normal range for at least 92 days. In contrast, without adjunct immunosuppression LDLR expression was transient, corresponding to temporary decline in cholesterol levels. Analysis of cholesterol concentrations in fractionated plasma showed remarkable reduction in all lipoprotein fractions at early time-points after gene transfer. At later time-points, non-immunosuppressed control mice regained the disease profile with elevated IDL/LDL cholesterol, while profiles of anti-CD154-treated mice were similar to normal. LDLR mRNA transcripts were present in livers of the anti-CD154-treated mice but not controls, 93 days after AdLDLR injection. However, vector DNA was detected in livers of both groups. These results suggest that loss of LDLR expression in the non anti-CD154-treated mice was in part due to immune-mediated promoter silencing, and that anti-CD154 prevented this effect. CONCLUSION: Treatment with anti-CD154 antibody inhibits immune-mediated loss of transgene expression, enabling long-term reduction in cholesterol levels after AdLDLR gene transfer to LDLR-deficient mice.

Adenoviridae↗
PubMedDate not supplied

Role of the mononuclear phagocyte system in the immunopathogenesis of human immunodeficiency virus infection and the acquired immunodeficiency syndrome.

In studies aimed at defining monocyte and macrophage function in patients with human immunodeficiency virus (HIV) infection, we found impaired in vivo Fc receptor-specific clearance in 20 of 25 patients with acquired immunodeficiency syndrome (AIDS) and in five of 13 patients with AIDS-related illnesses. The in vivo function of macrophage C3 receptors was also found to be abnormal: AIDS patients had a relatively large release of cell back into the circulation, suggesting failure of macrophage phagocytosis. The antibody-dependent cell-mediated cytotoxicity of circulating mononuclear cells was significantly lower in AIDS patients than in healthy controls. Monocyte nonspecific phagocytosis and surface marker expression were intact. Defective monocyte and macrophage function is an integral part of the immunopathology of AIDS, leading to the failure to control opportunistic pathogens. Whether these defects are due to intrinsic infection of the mononuclear phagocytes with HIV or are secondary to other events in the network of HIV infection remains to be determined.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Ultrasound-guided gene transfer to hepatocytes in utero.

OBJECTIVES: Several inherited liver diseases are associated with a progressive course that begins early in life. Such disorders may be amenable to treatment with gene transfer in the fetal or neonatal period. METHODS: We used ultrasound guidance to deliver an adenoviral vector to the liver of 28-day gestation fetal rabbits by cardiocentesis. beta-Galactosidase reporter gene expression in hepatocytes was analyzed 3, 7, and 21 days after vector delivery. Using this nonsurgical approach, the viral vector was efficiently delivered into the fetal circulation. RESULTS: The liver was the main organ targeted by this route of administration with up to 40% of the hepatocytes beta-galactosidase positive in some animals. The beta-galactosidase expression in hepatocytes gradually declined between 3 and 21 days following gene transfer. Associated with the decline in gene expression, an increased number of inflammatory cells were noted in the livers of adenoviral vector treated animals. This suggests that an immune response limits the duration of gene expression in the fetal rabbit, similar to the findings in postnatal animals. CONCLUSIONS: This animal model and vector delivery method may be useful for evaluating gene transfer to the fetus with viral and nonviral vectors. Further modifications of the adenoviral vector to reduce immunogenicity may enhance the duration of expression.

Adenoviridae↗