Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors.
E1-deleted adenoviral vectors are increasingly being utilized for in vivo gene transfer. The potential use of these vectors is limited by transient expression of the transgene and a markedly reduced rate of transduction following readministration, presumably due to a host immune response to the vector. We hypothesized that CD4+ lymphocytes are necessary to generate an immune response to these vectors and that administration of a depleting anti-CD4 antibody (GK1.5) might prolong transgene expression in vivo. We found that pretreatment of mice with a single injection (transient depletion) or weekly injections of GK1.5 (persistent depletion), markedly prolonged expression of an adenovirus-encoded tumor necrosis factor (TNF) inhibitor or luciferase gene compared to controls. Moreover, mice treated with GK1.5 showed no antiadenoviral antibody response to repeat administration of the vector and a second adenoviral transgene could be expressed in these animals. However, control mice developed a significant neutralizing antibody response that prevented transgene expression with administration of a second adenovirus. These findings demonstrate that manipulation of the host immune response may expand potential applications of gene transfer utilizing adenoviral vectors.
Kolls
J K
JK
LSU Department of Pediatrics, LSU Medical Center, New Orleans 70112, USA.
Lei
D
D
Odom
G
G
Nelson
S
S
Summer
W R
WR
Gerber
M A
MA
Shellito
J E
JE
D017498:Adenovirus E1 Proteins / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000917:Antibody Formation; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D017353:Gene Deletion; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008099:Liver / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D013997:Time Factors; D019076:Transgenes
D017498:Adenovirus E1 Proteins; D000911:Antibodies, Monoclonal; D017931:DNA Primers