Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors

D. M. Appledorn, A. McBride, S. Seregin, J. M. Scott, Nathan Schuldt, A. Kiang, S. Godbehere, A. Amalfitano

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

The complement system is known to play critical roles in pathogen identification, initiation of innate immune responses and facilitation of adaptive immune responses. Several studies have suggested that recombinant adenoviruses (rAds) interact with proteins of the complement system within minutes of administration. In this study, we assessed the roles of the alternative (Factor B), classical (C1q and C4) and common (C3) arms of the complement system in the innate and humoral response to systemic rAd administration using mice genetically deficient for each of these functions. Although most plasma cytokines and chemokines induced by Ads appeared to be elicited in a C3-dependent manner, we found that rAd-induced thrombocytopenia was dependent on Factor B and C3, implicating the alternative pathway as responsible for this response. Alteration of the complement-dependent transcriptome response after rAd-induced liver gene expression was also found to be Factor B- and C3-dependent. Ad interactions with the classical and alternative arms of the complement system can also be redundant, as many complement-dependent, Ad-induced innate immune responses appeared to be primarily C3-dependent. We also identified a C3 dependence of Ad-mediated induction of the nuclear factor-κB (NF-κB) activation pathway. Finally, we confirmed that humoral immune responses to the vector capsid, and the transgene it encodes, are also complement-dependent.

Original languageEnglish (US)
Pages (from-to)1606-1617
Number of pages12
JournalGene therapy
Volume15
Issue number24
DOIs
StatePublished - 2008
Externally publishedYes

Bibliographical note

Funding Information:
We thank Z Hartman, A Sisk, D Serra, K Porter, S Patial and N Parameswaran for technical support, and both the Duke University and Michigan State University Laboratory Animal support facilities for their assistance in the humane care and maintenance of the animals used in this work. AA was supported by the National Institutes of Health Grants RO1DK-069884 and P01 CA078673, as well as by the Osteopathic Heritage Foundation.

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