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Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo

Gene Therapy volumeĀ 9,Ā pages 220ā€“226 (2002)Cite this article

Abstract

We investigated the delivery of a donor-specific MHC class I gene, H-2Kb, using a newly constructed replication-defective recombinant adenovirus (AdSV40Kb) to recipient tissue before transplantation as a means of inducing donor-specific immunological unresponsiveness. AdSV40Kb was able to transduce both a fibroblast cell line and freshly isolated bone marrow cells (BMCs) resulting in cell surface expression of H2-Kb protein. Intravenous infusion of AdSV40Kb-transduced syngeneic CBA/Ca (H-2k) BMCs into CBA recipient mice treated with an anti-CD4 monoclonal antibody 27 days before transplantation of a fully MHC-mismatched, C57BL/10 (H-2Kb+), cardiac allograft resulted in significant long-term graft survival when compared with mice receiving the same dose of syngeneic BMCs transduced with a control adenovirus, AdRSVĪ²gal. Despite the induction of H-2Kb-specific hyporesponsiveness following pretreatment with AdSV40Kb-transduced CBA BMCs, persistence of H-2Kb mRNA in central or peripheral tissues could not be demonstrated by RT-PCR. This result was in contrast to the observed persistence of Kb mRNA both in the periphery and thymus following the infusion of transgenic CBK (H-2k + Kb) BMCs. We conclude that ex vivo adenoviral gene transfer of a single donor MHC class I gene to recipient BMCs in combination with transient depletion of CD4+ cells is sufficient to induce long-term graft survival of a fully allogeneic cardiac graft. In addition, detectable microchimerism is not a prerequisite for graft survival.

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Acknowledgements

This work was supported by the Wellcome Trust, The Medical Research Council of the United Kingdom and the European Union. The authors would like to thank Marco-Antonio Reis e Moura for technical assistance with the cardiac transplantation.

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  1. Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK

    JW Fry,Ā PJ MorrisĀ &Ā KJ Wood

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Fry, J., Morris, P. & Wood, K. Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo. Gene Ther 9, 220ā€“226 (2002). https://doi.org/10.1038/sj.gt.3301648

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