Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity.
In an earlier study we evaluated innate immune responses to a first-generation adenoviral vector infused into the portal vein of rhesus monkeys who had never been exposed to adenovirus previously. In these animals, the systemic administration of E1/E3-deleted adenoviral vectors resulted in immediate activation of innate immunity and serious toxicity caused by targeting of vector to antigen-presenting cells and systemic inflammation. We analyze here how these responses are affected by vector-specific preexisting immunity that was induced by intramuscular immunization 6 months prior to evaluation. Our results show that preexposure to the vector substantially diminishes the transgene expression in most tissues but has little effect on gene transfer. Significantly, preimmunization does not eliminate systemic vector-induced toxicity. These conclusions are based on the presence of clinical features of coagulopathy and elevated levels of proinflammatory cytokine interleukin-6 in the serum of animals treated with vector after intramuscular immunization. Furthermore, preexisting immunity appears to induce a vector-specific inhibitory effect on erythroid progenitor development in the bone marrow that is not found when naive animals are challenged with vector.
Varnavski
Andrei N
AN
Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania and The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Zhang
Yi
Y
Schnell
Michael
M
Tazelaar
John
J
Louboutin
Jean-Pierre
JP
Yu
Qian-Chun
QC
Bagg
Adam
A
Gao
Guang-ping
GP
Wilson
James M
JM
D000260:Adenoviruses, Human / Q000276:immunology* / Q000472:pathogenicity; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D015672:Erythroid Precursor Cells / Q000166:cytology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D007114:Immunization; D015850:Interleukin-6 / Q000097:blood; D008253:Macaca mulatta; D019076:Transgenes
D000914:Antibodies, Viral; D015850:Interleukin-6