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Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene

Gene Therapy volume 16, pages 1138–1145 (2009)Cite this article

Abstract

A major issue in long-term gene therapy is host immune responses to therapeutic cells when transgene encodes a potential antigen. The nature of these responses depends on several factors including the type of cell and tissue expressing the transgene. Keratinocytes and fibroblasts, which are known to display distinct immunogenic profiles, are both potential targets for transgene expression in cutaneous gene therapy. However, whether there is an immunological advantage in targeting one cell type over the other is not known. To study the effect of cell type on transgene-specific host responses independent of antigen levels or methods of gene transfer and transplantation, we used a skin transplantation model in which transgene expression can be targeted transgene to either keratinocytes or fibroblasts. Although targeting an antigen to either cell type resulted in the induction of immune responses, these responses differed significantly. Transgenic keratinocytes were rejected acutely by a dominant Th2 response, while in the majority of grafted animals transgenic fibroblasts failed to induce acute rejection despite the induction of Th1 type inflammation in the graft. In a small number of mice, transgenic fibroblasts persisted for at least 20 weeks despite elicitation of antigen-specific responses. Therefore, fibroblasts may be an immunologically preferred target over keratinocytes for cutaneous gene therapy.

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Acknowledgements

This research was supported by Grant R01-AR050525 from the National Institute of Health to SG.

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Authors and Affiliations

  1. Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, NY, Stony Brook, USA

    Z Zhang, C Kuscu & S Ghazizadeh

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  1. Z Zhang
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  2. C Kuscu
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  3. S Ghazizadeh
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Correspondence to S Ghazizadeh.

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

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Zhang, Z., Kuscu, C. & Ghazizadeh, S. Transgene-specific host responses in cutaneous gene therapy: the role of cells expressing the transgene. Gene Ther 16, 1138–1145 (2009). https://doi.org/10.1038/gt.2009.67

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