Inflammatory damage following first-generation replication-defective adenovirus controlled by anti-LFA-1.
First-generation replication-defective adenoviruses have been reported to lead to transient reporter gene expression due to a specific immune reaction involving T and B lymphocytes. Some recent reports have also demonstrated the presence of a nonspecific inflammatory reaction involving macrophages and neutrophils after both intramuscular injections and viral vectors transduction. To further investigate this nonspecific inflammatory reaction, deltaE1/E3a adenoviruses were injected intramuscularly in immunocompetent mice. Some of these mice were treated with anti-LFA-1. The adenovirus-injected muscles showed abundant CD4+, CD8+, LFA-1+, and Mac-1+ cell infiltration 3 days after the deltaE1/E3a injection. The anti-LFA-1 monoclonal antibody was able to block the nonspecific inflammatory damage due mostly to neutrophils and macrophages. The anti-LFA-1 did not produce this effect by reducing the muscle infiltration by LFA-1+ cells. It may instead have blocked the direct interaction between LFA-1 and ICAM-1 thus preventing the damage produced by the respiratory burst of neutrophils. Blocking the resulting damage of this inflammatory reaction with anti-LFA-1 in animals also treated with FK506, a powerful immunosuppressant for gene therapy, largely increased the long-term transgene expression compared with mice only treated with FK506.
Guérette
B
B
Centre de Recherche en Neurobiologie, Université Laval and Hôpital del'Enfant-Jésus, Québec, Canada.
Moisset
P A
PA
Huard
C
C
Tardif
F
F
Gravel
C
C
Tremblay
J P
JP
D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D014779:Virus Replication
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D016559:Tacrolimus