Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus.
The anti-CD40 ligand antibody MR-1, and macrophage-depleting liposomes were tested for their ability as transient immunosuppressive agents to: (1) prolong transgene expression; and (2) permit redosing after recombinant adenovirus infusion of mice. To test for effect on transgene duration, mice were infused with recombinant adenovirus coding for human factor IX (AdFIX), and plasma FIX levels monitored over time. Treatment with either agent significantly prolonged transgene expression. Persistence was accompanied by inhibition of anti-adenovirus (anti-Ad) IgG, and decreased IL-10 and IFN-gamma production from splenic lymphocytes re-exposed to virus particles in vitro. To test for effect on redosing, mice were given a primary infusion of recombinant adenovirus coding for bacterial beta-galactosidase (Ad beta gal), followed by secondary and tertiary infusions of AdFIX on days 24 and 63. Mice that had received MR-1 had low to undetectable anti-Ad on day 24, and efficient transduction occurred. Furthermore, FIX levels endured in these mice, with 40% retention of FIX on day 63, in contrast to rapid loss in naive controls. On day 63, the continuance of negligible anti-Ad levels correlated with successful tertiary transduction. These results suggest that both macrophage depletion and CD40 ligand blockade inhibit immune responses to recombinant adenovirus to slow decline of transgene expression, while only CD40 ligand blockade inhibits anti-Ad antibody generation sufficiently to allow redosing to the liver.
Stein
C S
CS
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Pemberton
J L
JL
van Rooijen
N
N
Davidson
B L
BL
D000256:Adenoviridae; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D004002:Clodronic Acid / Q000494:pharmacology; D005164:Factor IX / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000032:analysis; D007165:Immunosuppression Therapy; D007267:Injections; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008264:Macrophages; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D013997:Time Factors; D019076:Transgenes
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007074:Immunoglobulin G; D008081:Liposomes; D004002:Clodronic Acid; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D005164:Factor IX