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Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival

Gene Therapy volume 13, pages 1104–1109 (2006)Cite this article

Abstract

Vascularized organ allografts are rapidly destroyed by host immune cells that are recruited along chemokine gradients. Among chemokines, Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) CC chemokine ligand (CCL5) and monocyte chemoattractant protein (MCP)-1 (CCL2) are upregulated in rejecting cardiac allografts. To antagonize these chemokines, we constructed adenoviral vectors expressing NH2-terminal deletion (8ND) mutants of the respective genes. Using the F344-to-LEW rat model, intragraft gene transfer of chemokine analogs prolonged cardiac allograft survival from 10.1±0.7 and 10.4±0.7 days using non-coding adenovirus and vehicle alone, respectively, to 17.0±0.7 days for 8ND-RANTES (P<0.001) and 14.2±0.8 days for 8ND-MCP-1 (P<0.01). 8ND-RANTES reduced graft infiltration by monocytes/macrophages, cluster of differentiation (CD) 8α+ and T-cell receptor αβ+ cells, while 8ND-MCP-1 reduced monocytes/macrophages. In mixed leukocyte reactions in vitro, proliferation of host lymphocytes from regional lymph nodes in response to donor splenocytes was unaffected by 8ND-RANTES gene transfer. Using a two-gene approach, the contribution of 8ND-MCP-1 was negligible, consistent with available evidence that 8ND-RANTES inhibits both RANTES and MCP-1 activities. 8ND-RANTES gene transfer and a short course of low-dose cyclosporine A synergistically prolonged graft survival to 37.8±5.5 vs 15.4±0.5 days with cyclosporine alone (P<0.001). These results suggest a role for anti-chemokine gene therapy as an adjuvant therapy in heart transplantation.

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Acknowledgements

This work was supported by Swiss National Science Foundation research grants #632-058215 (to GV) and #3100-064.834.01 (to SF), the Lausanne Foundation of Cardiac Transplantation, the Swiss Cardiology Foundation, and the Teo Rossi di Montelera Foundation, Lausanne, Switzerland.

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Authors and Affiliations

  1. Department of Cardiology, University Hospital, Lausanne, Switzerland

    S Fleury, J Li, E Simeoni, E Fiorini, L Kappenberger & G Vassalli

  2. Department of Experimental Surgery, University Hospital, Lausanne, Switzerland

    S Fleury & E Simeoni

  3. Transplantation Research, Novartis Institutes for Biomedical Research, Basel, Switzerland

    J Li

  4. Institute of Microbiology, University Hospital, Lausanne, Switzerland

    E Fiorini & G Vassalli

  5. Department of Cardiovascular Surgery, University Hospital, Lausanne, Switzerland

    L K von Segesser

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  1. S Fleury
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  3. E Simeoni
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  4. E Fiorini
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Correspondence to G Vassalli.

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Fleury, S., Li, J., Simeoni, E. et al. Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival. Gene Ther 13, 1104–1109 (2006). https://doi.org/10.1038/sj.gt.3302765

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