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  • Viral Transfer Technology
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Gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity

Gene Therapy volume 7, pages 575–582 (2000)Cite this article

Abstract

Introducing immunomodulatory molecules into allografts by gene transfer may avoid the side-effects of systemic immunosuppression. vMIP-II and MC148 are two recently identified chemokine homologues encoded by human herpes virus 8 and Molluscum contagiosum, respectively, that have antagonistic activities against multiple different CC and CXC chemokine receptors. We hypothesized that introduction of these molecules into cardiac allografts may block leukocyte infiltration into the grafts and prolong survival. Vascularized and nonvascularized cardiac allografts in mice were performed and plasmid DNA encoding vMIP-II, MC148 and/or vIL-10 was transferred into the allograft at the time of transplantation. Gene transfer of either vMIP-II or MC148 into cardiac allografts markedly prolonged graft survival. Combining gene transfer of either one of these chemokine antagonists with vIL-10 gene transfer, which has a mechanistically different immunosuppressive action, further enhanced graft survival. vMIP-II and MC148 gene transfer both resulted in a marked decrease of donor-specific cytotoxic T lymphocytes (CTL) infiltrating the grafts and inhibited alloantibody production. These results demonstrate that plasmid-mediated gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 can block donor-specific lymphocyte immunity within cardiac allografts and prolong graft survival. This is a new mechanistic approach to analyze, treat, and prevent graft rejection. Delivery of these or related molecules by gene transfer or conventional pharmacologic means may represent a novel therapeutic modality for alloactivation.

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Acknowledgements

We thank Dr John Magee for stimulating discussions and critical comments during the preparation of this manuscript. This work is supported in part by the National Institutes of Health T32 AI-07413 (LAD), RO1 AI-31946 (DKB), UM MAC P60-AR20557 (JSB); Edward Mallinckrodt, Jr Foundation (JSB); and the Baxter Extramural Grant Program (JSB).

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Authors and Affiliations

  1. Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, USA

    L A DeBruyne, K Li, D K Bishop & J S Bromberg

  2. Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, MI, USA

    D K Bishop & J S Bromberg

  3. The Recanati-Miller Transplant Institute, Mount Sinai School of Medicine, New York, NY, USA

    J S Bromberg

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  1. L A DeBruyne
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  2. K Li
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DeBruyne, L., Li, K., Bishop, D. et al. Gene transfer of virally encoded chemokine antagonists vMIP-II and MC148 prolongs cardiac allograft survival and inhibits donor-specific immunity. Gene Ther 7, 575–582 (2000). https://doi.org/10.1038/sj.gt.3301128

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