[Adenovirus induced acute hepatitis in non-human primates after liver- directed gene therapy].

Abstract

OBJECTIVE:

To define the role of lymphocyte subsets and investigate the efficiency of immunosuppression regimen in acute hepatitis in non-human primates after adenovirus mediated gene therapy.

METHODS:

Six rhesus monkeys were infused with E-1 deleted adenovirus (Ad) expressing E coli lacZ gene or luciferase by various routes. Four of 6 animals were immunosuppressed by cyclophosphamide and predenisone. Two monkeys were transfected with a lacZ containing plasmid with lipofectamine as the control. Lymphocyte subsets CD3, CD4, CD8, CD20 and MHC molecule beta2-microglobulin(beta2-MG) and HLA-DR in liver tissues were studied using immunohistochemical staining.

RESULTS:

Staining of beta2-MG and HLA-DR on the membranes of hepatocyte and increased numbers of CD3+, CD4+ and CD8+ T-lymphocytes were detected in the livers after gene transfer, while B-lymphocytes were absent. The monkeys developed a mild to moderate transient hepatitis. This was accompanied by adenovirus-mediated T-cell proliferation and neutralizing antibodies to adenovirus. Drug-induced immune suppression enhanced the ability of adenovirus- mediated gene transfer. The development of acute hepatitis and the accompanying immune abnormalities were delayed in immunosuppressed monkeys until after discontinuation of immunosuppressive therapy. Lipofectamine-mediated gene transfer was inefficient and no immune response and liver damage were observed in the livers.

CONCLUSIONS:

Increased numbers of beta2-MG, HLA-DR, CD3, CD4 and CD8 antigen positive cells are presented in the monkey livers after adenovirus-mediated gene therapy and induce mild to moderate transient hepatic inflammation. Immunosuppression regimen may prolong transgene expression and delay the development of acute adenoviral hepatitis.

• Authors: H Lu, D Sullivan, S Dash
• Journal: Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology (Zhonghua Gan Zang Bing Za Zhi) Vol. 9 Issue 5 Pg. 291-3 (Oct 2001) ISSN: 1007-3418 [Print] China
• PMID: 11676876 (Publication Type: Journal Article)

Chemical References

• Antigens, CD
• HLA-DR Antigens
• Immunosuppressive Agents

Topics

• Adenoviridae (genetics, pathogenicity)
• Adenoviridae Infections (immunology)
• Animals
• Antigens, CD (immunology)
• Disease Models, Animal
• Gene Expression (drug effects)
• Genetic Therapy (adverse effects)
• Genetic Vectors
• HLA-DR Antigens (immunology)
• Hepatovirus (immunology)
• Immunosuppression Therapy
• Immunosuppressive Agents (pharmacology)
• Macaca mulatta
• Male
• T-Lymphocyte Subsets (immunology)
• Transgenes (drug effects)