Nondepleting anti-CD4 antibody treatment prolongs lung-directed E1-deleted adenovirus-mediated gene expression in rats.
E1-deleted adenoviral vectors are efficient vectors for somatic cell gene therapy, but transgene expression is limited in part by a cytotoxic T cell response directed against virally transduced cells. Moreover, the development of a neutralizing antibody response limits secondary gene transfer with these vectors. Therapy with a depleting anti-CD4 antibody permits prolonged transgene expression in the lung and liver of mice. Furthermore, transient depletion of CD4+ lymphocytes blocks neutralizing antibody production and therefore allows repeat administration and expression of E1-deleted recombinant adenovirus. In this study, we investigated the efficacy of a novel nondepleting anti-CD4 antibody (RIB 5/2) in a model of lung-directed gene therapy in outbred rats. Treatment with RIB 5/2 permitted prolonged reporter gene expression and reduced adenovirus-induced peribronchial and alveolar inflammation in the lung. Moreover administration of RIB 5/2 blocked the development of an anti-adenoviral neutralizing antibody response in the lung and permitted secondary administration and expression of a recombinant adenovirus. These data support the role of immunomodulation in prolonging in vivo transgene expression by recombinant adenovirus.
Lei
D
D
LSU Section of Pulmonary/Critical Care MEB, New Orleans 70112, USA.
Lehmann
M
M
Shellito
J E
JE
Nelson
S
S
Siegling
A
A
Volk
H D
HD
Kolls
J K
JK
D017498:Adenovirus E1 Proteins; D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral / Q000032:analysis / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D016131:Lymphocyte Subsets; D008297:Male; D009500:Neutralization Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001616:beta-Galactosidase / Q000235:genetics
D017498:Adenovirus E1 Proteins; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D008156:Luciferases; D001616:beta-Galactosidase