Cytotoxic immune response after retroviral-mediated hepatic gene transfer in rat does not preclude expression from adeno-associated virus 1 transduced muscles.
Intravenous delivery of nls-lacZ retroviral vectors to the regenerating liver triggers a cytotoxic immune response directed against transduced hepatocytes. We sought to determine whether prior immunization with retroviral vectors impacted on adeno-associated virus (AAV)-mediated muscular expression of the same transgene. The first group of rats first received nls-lacZ retroviral vectors intravenously after a partial hepatectomy. Thirty days later they received AAV vectors intramuscularly in both legs. In the second group, animals received the same vectors in the opposite sequence (i.e., AAV first and retroviruses 20 days later). In the first group, immune response occurred after retrovirus delivery with appearance of anti-beta-galactosidase antibodies and elimination of transduced hepatocytes. However, the immune response did not prevent sustained (9-month) beta-galactosidase expression in AAV-injected muscles. In the second group, AAV injections did not induce immune response and resulted in beta-galactosidase expression in myofibers. In this group, subsequent delivery of retroviral vectors triggered appearance of immune response and elimination of transduced hepatocytes. However, the immune response did not modify beta-galactosidase expression in AAV-transduced myofibers for up to 9 months. These results demonstrate a differential susceptibility between retrovirally transduced liver and AAV-transduced muscles to immune response against the transgene product.
Aubert
Dominique
D
Laboratoire de Thérapie Génique, INSERM ERM 0105, CHU Hotel-Dieu, 44035 Nantes, France.
Pichard
Virginie
V
Durand
Sophie
S
Moullier
Philippe
P
Ferry
Nicolas
N
D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage; D006498:Hepatectomy; D007114:Immunization; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D012190:Retroviridae / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D001616:beta-Galactosidase