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Muscle stem cells can act as antigen-presenting cells: implication for gene therapy

Gene Therapy volume 11, pages 1321–1330 (2004)Cite this article

Abstract

Research has shown that the use of a muscle-specific promoter can reduce immune response and improve gene transfer to muscle fibers. We investigated the efficiency of direct and ex vivo gene transfer to the skeletal muscles of 6- to 8-week-old mdx mice by using two adenoviral vectors: adenovirus (AD) encoding the luciferase gene under the cytomegalovirus (CMV) promoter (ADCMV) and AD encoding the same gene under the muscle creatine kinase (MCK) promoter (ADMCK). Direct intramuscular injection of ADMCK triggered a lower immune response that enabled more efficient delivery and more persistent expression of the transgene than did ADCMV injection. Similarly, ex vivo gene transfer using ADCMV-transduced muscle-derived stem cells (MDSCs) induced a stronger immune response and led to shorter transgene expression than did ex vivo gene transfer using ADMCK-transduced MDSCs. This immune response was due to the release of the antigen after MDSC death or to the ADCMV-transduced MDSCs acting as antigen-presenting cells (APCs) by expressing the transgene and rapidly initiating an immune response against subsequent viral inoculation. The use of a muscle-specific promoter that restricts transgene expression to differentiated muscle cells could prevent MDSCs from becoming APCs, and thereby could improve the efficiency of ex vivo gene transfer to skeletal muscle.

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Acknowledgements

This work was supported by the Muscular Dystrophy Association (USA) and the National Institutes of Health (NIH P01 AR 45925-01). The Growth and Development Laboratory is also supported by the Henry J Mankin Endowed Chair at the University of Pittsburgh and the William F and Jean W Donaldson Chair at Children's Hospital of Pittsburgh. We thank James Cummins, Marcelle Pellerin, Jessica Tebbets, and Arvydas Usas for their technical contributions. We also thank Dr Nick Giannoukakis (Division of Immunogenetics, Children's Hospital of Pittsburgh) for technical help and Ryan Sauder for excellent editorial assistance with the manuscript.

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Authors and Affiliations

  1. Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, Growth and Development Laboratory, University of Pittsburgh, Pittsburgh, PA, USA

    B Cao & J Huard

  2. GenVec, Inc., Gaithersburg, MD, USA

    J Bruder

  3. KILA Consultants, LLC, Rockville, MD, USA

    I Kovesdi

  4. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

    J Huard

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Cao, B., Bruder, J., Kovesdi, I. et al. Muscle stem cells can act as antigen-presenting cells: implication for gene therapy. Gene Ther 11, 1321–1330 (2004). https://doi.org/10.1038/sj.gt.3302293

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