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Eur J Cardiothorac Surg 2006;29:779-783
© 2006 Elsevier Science NL

Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model

^a Department of Cardiology, University of Lausanne Medical Hospital, Lausanne, Switzerland
^b Department of Experimental Surgery, University of Lausanne Medical Hospital, Lausanne, Switzerland
^c Department of Rheumatology, University of Lausanne Medical Hospital, Lausanne, Switzerland
^d Department of Cardiovascular Surgery, University of Lausanne Medical Hospital, Lausanne, Switzerland
^e Department of Microbiology, University of Lausanne Medical Hospital, Lausanne, Switzerland
^f The Organ Transplantation Center, University of Lausanne Medical Hospital, Lausanne, Switzerland
^g Transplantation Research, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland

Received 25 November 2005; received in revised form 16 January 2006; accepted 17 January 2006.

^_* Corresponding author. Address: CHUV, BH10, rue de Bugnon, 1011 Lausanne, Switzerland. Tel.: +41 21 3140076; fax: +41 21 3140013. (Email: giuseppe.vassalli{at}chuv.hospvd.ch).

Objective: Interleukin-17 (IL-17), a potent proinflammatory cytokine, has been implicated in allograft rejection. We analyzed the efficacy of an adenoviral vector expressing an IL-17 inhibitor in delaying acute allograft rejection in a rat model of heart transplantation, and the biological mechanisms underlying the protective effect. Methods: We constructed an adenoviral vector expressing a soluble IL-17 receptor-immunoglobulin (IL-17R-Ig) fusion protein. IL-17R-Ig activity was assessed by inhibition of IL-17-induced IL-6 release in HeLa cells preincubated with the vector. Intracoronary vector administration was performed in F344 donor hearts that were placed as vascularized grafts into Lewis hosts. Inflammatory cells infiltrating the graft were analyzed by immunohistology. Cytokine transcripts in the graft were determined by real-time RT-PCR. Results: IL-17R-Ig gene transfer resulted in prolonged allograft survival (16.1 ± 3.1 days vs 10.3 ± 2.5 days with control virus and 10.1 ± 2.1 days with virus dilution buffer alone; p < 0.001). IL-17R-Ig gene transfer reduced inflammatory cell infiltrates, especially monocytes/macrophages and CD4⁺ T cells (p < 0.05). It also reduced intragraft cytokine transcripts for interferon- and transforming growth factor-ß (p < 0.05) and, to a lesser extent, IL-1ß and tumor necrosis factor- (p = 0.083). Conclusions: Local expression of soluble IL-17 receptor-immunoglobulin attenuates T helper type 1 (Th1) cytokine responses and leukocyte infiltration in rat cardiac allografts, thereby mediating prolonged graft survival. Intragraft IL-17 inhibition may be useful as an adjuvant therapy to systemic immunosuppression in heart transplantation.

Key Words: Heart transplantation • Cytokine • IL-17 • IL-17R • Gene therapy

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