Humoral and cellular immune responses of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2.
To evaluate the host immune response to long-term repeat administration of adenovirus vector, rhesus monkeys were treated at intervals of approximately 3 weeks with up to 18 instillations of Ad2/CFTR-2, a second generation vector encoding the cystic fibrosis transmembrane conductance regulator (CFTR). All monkeys instilled with Ad2/CFTR-2 developed a significant humoral immune response against adenovirus but not CFTR. Antibodies with virus neutralizing activity were detected in the serum and bronchoalveolar lavage (BAL) of all vector-treated monkeys and included both IgG and secretory IgA. Virus-specific T cells capable of proliferating in response to stimulation with adenovirus antigen were detected in all vector-treated monkeys. No CFTR-specific proliferation of peripheral blood lymphocytes was detected. An increase in the proportion of CD8+ T cells was noted in the BAL of virus-treated monkeys but cells from the BAL displayed little or no cytolytic activity against infected autologous fibroblasts when tested under a variety of culture conditions. However, MHC-restricted cytolytic activity was detected in the tracheobronchial lymph nodes and spleen of one of three virus-treated monkeys tested. MHC-unrestricted killing of infected fibroblasts was also observed with spleen cells from all animals tested. From these results, it appears that both the humoral and cell-mediated arms of the immune response were stimulated by repeated administration of high doses of Ad2/CFTR-2 suggesting that effective, long-term adenovirus gene therapy may require modification of the vector or treatment of the host to allow the virus to evade host immune defenses.
Kaplan
J M
JM
Genzyme Corporation, Framingham, MA 01701-9322, USA.
St George
J A
JA
Pennington
S E
SE
Keyes
L D
LD
Johnson
R P
RP
Wadsworth
S C
SC
Smith
A E
AE
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis* / Q000097:blood; D015703:Antigens, CD / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003550:Cystic Fibrosis / Q000276:immunology / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D007070:Immunoglobulin A / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D009500:Neutralization Tests; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000914:Antibodies, Viral; D015703:Antigens, CD; D007070:Immunoglobulin A; D019005:Cystic Fibrosis Transmembrane Conductance Regulator