[Adenovirus induced acute hepatitis in non-human primates after liver- directed gene therapy].
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.
Lu
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Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New orleans, LA 70112, USA.
Sullivan
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Dash
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D000256:Adenoviridae / Q000235:genetics / Q000472:pathogenicity*; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D006684:HLA-DR Antigens / Q000276:immunology; D006507:Hepatovirus / Q000276:immunology*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019076:Transgenes / Q000187:drug effects
D015703:Antigens, CD; D006684:HLA-DR Antigens; D007166:Immunosuppressive Agents