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Antigen-specific humoral tolerance or immune augmentation induced by intramuscular delivery of adeno-associated viruses encoding CTLA4-Ig-antigen fusion molecules

Gene Therapy volume 16, pages 200–210 (2009)Cite this article

Abstract

This study initially sought to investigate the immunostimulatory properties of recombinant adeno-associated virus (rAAV) with a view to developing a genetic vaccine for malaria using muscle as a target tissue. To augment humoral immunity, the AAV-encoded antigen was genetically fused with CTLA4-Ig, a recombinant molecule that binds B7 costimulatory molecules. At 109 vg, CTLA4-Ig fusion promoted the humoral immune response 100-fold and was dependent on CTLA4-Ig binding with B7 costimulatory molecules, confirming plasmid DNA models using this strategy. In distinct contrast, 1012–1013 vg of rAAV1 specifically induced long-lived humoral tolerance through a mechanism that is independent of CTLA4-Ig binding with B7. This finding was unexpected, as rAAV delivery to muscle, unlike liver, has shown that this tissue provides a highly immunogenic environment for induction of humoral immunity against rAAV transgene products. An additional unpredicted consequence of antigen fusion with CTLA4-Ig was the enhancement of antigen expression by approximately one log, an effect mapped to the hinge and Fc domain of IgG1, but not involving antigen dimerization or the neonatal Fc receptor. Collectively, these findings significantly advance the potential of rAAV both as a vaccine or immunotherapeutic platform for the induction of antigen-specific humoral immunity or tolerance and as a gene therapeutic delivery system.

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Acknowledgements

We thank Dr Christine Smyth for her valuable expertize in flow cytometry and Ms Margot Latham for assistance in manuscript preparation. Samantha L Ginn is the recipient of a fellowship honoring the memory of Noel Dowling. This work was supported by a grant (477101) from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Gene Therapy Research Unit, Children's Medical Research Institute, Children's Hospital at Westmead, Wentworthville, New South Wales, Australia

    G J Logan, M Zheng, S L Ginn & I E Alexander

  2. Department of Microbiology, Victoria Bioinformatics Consortium, Monash University, Clayton, Australia

    L Wang & R L Coppel

  3. Discipline of Paediatrics and Child Health, The University of Sydney, Westmead, Australia

    I E Alexander

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  1. G J Logan
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Correspondence to I E Alexander.

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Logan, G., Wang, L., Zheng, M. et al. Antigen-specific humoral tolerance or immune augmentation induced by intramuscular delivery of adeno-associated viruses encoding CTLA4-Ig-antigen fusion molecules. Gene Ther 16, 200–210 (2009). https://doi.org/10.1038/gt.2008.168

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