Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model.
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-gamma and transforming growth factor-beta (p<0.05) and, to a lesser extent, IL-1beta and tumor necrosis factor-alpha (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.
Li
Jianping
J
Department of Cardiology, University of Lausanne Medical Hospital, Lausanne, Switzerland.
Simeoni
Eleonora
E
Fleury
Sylvain
S
Dudler
Jean
J
Fiorini
Emma
E
Kappenberger
Lukas
L
von Segesser
Ludwig K
LK
Vassalli
Giuseppe
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D018123:Receptors, Interleukin / Q000235:genetics / Q000502:physiology*; D053722:Receptors, Interleukin-17; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012995:Solubility
D016207:Cytokines; C491673:Il17ra protein, mouse; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17