Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus

C S Stein; J L Pemberton; N van Rooijen; B L Davidson

doi:10.1038/sj.gt.3300616

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Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus

Journal article

Open access

Peer reviewed

Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus

C S Stein, J L Pemberton, N van Rooijen and B L Davidson

Gene therapy, Vol.5(4), pp.431-439

04/01/1998

DOI: 10.1038/sj.gt.3300616

PMID: 9614566

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Abstract

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.

Adenoviridae

Animals

Antibodies, Monoclonal - pharmacology

CD40 Antigens - immunology

Clodronic Acid - pharmacology

Factor IX - analysis

Factor IX - genetics

Factor IX - immunology

Gene Expression

Genetic Therapy - methods

Genetic Vectors - administration & dosage

Immunoglobulin G - analysis

Immunosuppression

Injections

Interferon-gamma - secretion

Interleukin-10 - secretion

Interleukin-4 - secretion

Leukocytes - secretion

Liposomes

Liver - metabolism

Macrophages

Male

Mice

Mice, Inbred CBA

Time Factors

Transgenes

Details

Title: Subtitle: Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus
Creators: C S Stein - University of Iowa
J L Pemberton - University of Iowa
N van Rooijen - Vrije Universiteit Amsterdam
B L Davidson
Resource Type: Journal article
Publication Details: Gene therapy, Vol.5(4), pp.431-439
DOI: 10.1038/sj.gt.3300616
PMID: 9614566
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Grant note: HL07121 / NHLBI NIH HHS HD33531 / NICHD NIH HHS NS34568 / NINDS NIH HHS
Language: English
Date published: 04/01/1998
Academic Unit: Internal Medicine
Record Identifier: 9984618520102771

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