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Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine

Gene Therapy volume 19, pages 78–85 (2012)Cite this article

Abstract

The ability of transient immunosuppression with a combination of a non-depleting anti-CD4 (NDCD4) antibody and cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated viral vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2 × 1012 AAV8 vector particles per kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.

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Acknowledgements

This work was supported by The Katharine Dormandy Trust, UK, Medical Research Council, UK, Department of Health's NIHR Biomedical Research Centre's funding award to UCLH/UCL, UK, NIHR programme grant A for Molecular and Tissue Engineering. The ASSISI Foundation of Memphis, the American Lebanese Syrian Associated Charities (ALSAC), National Heart, Lung, and Blood Institute (NHLBI) Grant HL073838.

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Authors and Affiliations

  1. Department of Haematology, UCL Cancer Institute, University College London, Oxford, UK

    J H McIntosh, M Cochrane, S A Nathwani & A C Nathwani

  2. Sir William Dunn School of Pathology, Oxford, UK

    S Cobbold & H Waldmann

  3. Department of Surgery, St Jude Children's Research Hospital, Memphis, TN, USA

    A M Davidoff

  4. NHS Blood and Transplant, Oxford, UK

    A C Nathwani

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  1. J H McIntosh
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  2. M Cochrane
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Correspondence to A C Nathwani.

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Hermann Waldmann and Stephen Cobbold are shareholders in TolerRx Inc. The other authors declare no conflict of interest.

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McIntosh, J., Cochrane, M., Cobbold, S. et al. Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine. Gene Ther 19, 78–85 (2012). https://doi.org/10.1038/gt.2011.64

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