Immunomodulation with FK506 around the time of intravenous re-administration of an adenoviral vector facilitates gene transfer into primed rat liver.
Although adenoviruses are an attractive vehicle for gene transfer into tissues including various tumors, in vivo adenoviral administration elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Transiently immunosuppressive strategies at the time of initial adenoviral exposure have shown to prevent the formation of neutralizing antibodies and permit the successful adenoviral readministration in animals. Initial treatment in humans may, however, correspond to adenoviral readministration into animals, because the exposure to wild-type adenoviruses is common in humans. In the present study, we infused Adex1CAlacZ adenoviruses carrying the lacZ gene into the tail vein of rats, and examined whether a transient treatment with the immunosuppressant FK506 around the time of i.v. readministration of adenoviruses could induce the re-expression of the lacZ gene in animals primed with adenoviruses. Although i.v. infusion of adenoviruses carrying the lacZ gene resulted in transiently high levels of transgene expression in rat liver, i.v. reinfusion of adenoviruses failed to induce detectable levels of transgene expression. Conversely, when animals were treated transiently with FK506 around the time of adenoviral reinfusion, development of neutralizing antibodies and antigen-specific T cell proliferation in response to adenoviral reinfusion were significantly suppressed, and re-expression of the transgene was achievable.
Kuriyama
S
S
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Tominaga
K
K
Mitoro
A
A
Tsujinoue
H
H
Nakatani
T
T
Yamazaki
M
M
Nagao
S
S
Toyokawa
Y
Y
Okamoto
S
S
Fukui
H
H
D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007763:Lac Operon; D008099:Liver; D008213:Lymphocyte Activation; D009500:Neutralization Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes; D016559:Tacrolimus / Q000008:administration & dosage*; D019076:Transgenes
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D016559:Tacrolimus