1. ¹Department of Cardiology, University Hospital, Lausanne, Switzerland
2. ²Department of Experimental Surgery, University Hospital, Lausanne, Switzerland
3. ³Transplantation Research, Novartis Institutes for Biomedical Research, Basel, Switzerland
4. ⁴Institute of Microbiology, University Hospital, Lausanne, Switzerland
5. ⁵Department of Cardiovascular Surgery, University Hospital, Lausanne, Switzerland

Correspondence: Professor G Vassalli, Department of Cardiology, Centre Hospitalier Universitaire Vaudois (CHUV), rue du Bugnon, 1011 Lausanne, Switzerland. E-mail: giuseppe.vassalli@chuv.hospvd.ch

Received 30 November 2004; Revised 1 February 2006; Accepted 6 February 2006; Published online 16 March 2006.

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 10.10.7 and 10.40.7 days using non-coding adenovirus and vehicle alone, respectively, to 17.00.7 days for 8ND-RANTES (P<0.001) and 14.20.8 days for 8ND-MCP-1 (P<0.01). 8ND-RANTES reduced graft infiltration by monocytes/macrophages, cluster of differentiation (CD) 8⁺ and T-cell receptor ⁺ 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 37.85.5 vs 15.40.5 days with cyclosporine alone (P<0.001). These results suggest a role for anti-chemokine gene therapy as an adjuvant therapy in heart transplantation.