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

Gene Therapy volume 15, pages 1606–1617 (2008)Cite this article

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.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA

    D M Appledorn, A McBride, S Seregin, J M Scott, N Schuldt, S Godbehere & A Amalfitano

  2. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    A Kiang & A Amalfitano

  3. Department of Pediatrics, Michigan State University, East Lansing, MI, USA

    A Amalfitano

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  1. D M Appledorn
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Correspondence to A Amalfitano.

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Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Appledorn, D., McBride, A., Seregin, S. et al. Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors. Gene Ther 15, 1606–1617 (2008). https://doi.org/10.1038/gt.2008.114

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