Antibody to CD40 ligand inhibits both humoral and cellular immune responses to adenoviral vectors and facilitates repeated administration to mouse airway.
Adenoviral vectors have been used successfully to transfer the human CFTR cDNA to respiratory epithelium in animal models and to CF patients in vivo. However, studies done primarily in mice, indicate that present vector systems have limitations. Among other things, transgene expression in the lung is transient and the production of neutralizing antibodies against adenovirus correlates with a reduced ability to readminister a vector of the same serotype. Here we demonstrate that in mice, a transient blockade of costimulation between activated T cells and B cells/antigen presenting cells using a monoclonal antibody (MR1) against murine CD40 ligand inhibits the development of neutralizing antibodies to adenoviral (Ad) vector. MR1 also decreased the cellular immune response to Ad vector and allowed an increase in persistence of transgene expression. Furthermore, when administered with a second dose of Ad vector to mice preimmunized against vector, MR1 was able to interfere with the development of a secondary antibody response and allowed for high levels of transgene expression upon a third administration of vector to the airway.
Scaria
A
A
Genzyme Corporation, Framingham, MA 01701, USA.
St George
J A
JA
Gregory
R J
RJ
Noelle
R J
RJ
Wadsworth
S C
SC
Smith
A E
AE
Kaplan
J M
JM
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation; D019013:CD40 Antigens / Q000276:immunology*; D003550:Cystic Fibrosis / Q000276:immunology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000276:immunology; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D019076:Transgenes
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens