An immunomodulatory procedure that stabilizes transgene expression and permits readministration of E1-deleted adenovirus vectors.
Immune responses against E1-deleted adenovirus vectors and/or their transgene products result in the rapid elimination of vector-transduced cells and the generation of neutralizing antibodies. Different strategies of immunomodulation to stabilize transgene expression at therapeutic levels and to permit productive vector readministration have been examined. Our previous studies have shown that depletion of macrophages from spleen and liver decreases hepatic inflammation, significantly prolongs transgene expression, and delays the onset of humoral immune responses after systemic administration of an E1-deleted adenovirus vector. In the present study, we have examined the effects of macrophage depletion in combination with temporary blockade of CD40 ligation on E1-deleted adenovirus vector-mediated gene transfer. Alone, each of these treatments significantly inhibited the humoral immune response against the transgene product and prolonged its expression. Together, these treatments completely stabilized transgene expression and inhibited the production of neutralizing anti-adenovirus antibodies, permitting successful vector readministration. Animals rendered immunologically unresponsive to vector and transgene antigens regained their ability to mount productive immune responses against the vector after recovery of immune function, but remained unresponsive to the transgene product. These experiments demonstrate that this treatment is transient and antigen-specific.
Institute for Gene Therapy and Molecular Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USA.
A I
AI
Kuzmin
O
O
Galenko
R C
RC
Eisensmith
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D004002:Clodronic Acid / Q000008:administration & dosage; D005620:Freund's Adjuvant / Q000008:administration & dosage; D017353:Gene Deletion; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology*; D007111:Immunity, Cellular; D007165:Immunosuppression Therapy; D008081:Liposomes; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012965:Sodium Chloride; D013997:Time Factors; D019076:Transgenes
D017498:Adenovirus E1 Proteins; D000906:Antibodies; D019013:CD40 Antigens; D008081:Liposomes; D004002:Clodronic Acid; D012965:Sodium Chloride; D005620:Freund's Adjuvant