Gene transfer of a soluble IL-1 type 2 receptor-Ig fusion protein improves cardiac allograft survival in rats.

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Serval ID
serval:BIB_F23777167549
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Gene transfer of a soluble IL-1 type 2 receptor-Ig fusion protein improves cardiac allograft survival in rats.
Journal
European Journal of Cardio-thoracic Surgery
Author(s)
Simeoni E., Dudler J., Fleury S., Li J., Pagnotta M., Pascual M., von Segesser L.K., Vassalli G.
ISSN
1010-7940
Publication state
Published
Issued date
2007
Peer-reviewed
Oui
Volume
31
Number
2
Pages
222-228
Language
english
Abstract
OBJECTIVE: Interleukin-1 (IL-1) mediates ischemia-reperfusion injury and graft inflammation after heart transplantation. IL-1 affects target cells through two distinct types of transmembrane receptors, type-1 receptor (IL-1R1), which transduces the signal, and the non-signaling type-2 receptor (IL-1R2), which acts as a ligand sink that subtracts IL-1beta from IL-1R1. We analyzed the efficacy of adenovirus (Ad)-mediated gene transfer of a soluble IL-1R2-Ig fusion protein in delaying cardiac allograft rejection and the mechanisms underlying the protective effect. METHODS: IL-1 inhibition by IL-1R2-Ig was tested using an in vitro functional assay whereby endothelial cells preincubated with AdIL-1R2-Ig or control virus were stimulated with recombinant IL-1beta or tumor necrosis factor-alpha (TNF-alpha), and urokinase-type plasminogen activator (u-PA) induction was measured by zymography. AdIL-1R2-Ig was delivered to F344 rat donor hearts ex vivo, which were placed in the abdominal position in LEW hosts. Intragraft inflammatory cell infiltrates and proinflammatory cytokine expression were analyzed by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: IL-1R2-Ig specifically inhibited IL-1beta-induced u-PA responses in vitro. IL-1R2-Ig gene transfer reduced intragraft monocytes/macrophages and CD4(+) cell infiltrates (p<0.05), TNF-alpha and transforming growth factor-beta (TGF-beta) expression (p<0.05), and prolonged graft survival (15.6+/-5.7 vs 10.3+/-2.5 days with control vector and 10.1+/-2.1 days with buffer alone; p<0.01). AdIL-1R2-Ig combined with a subtherapeutic regimen of cyclosporin A (CsA) was superior to CsA alone (19.4+/-3.0 vs 15.9+/-1.8 days; p<0.05). CONCLUSIONS: Soluble IL-1 type-2 receptor gene transfer attenuates cardiac allograft rejection in a rat model. IL-1 inhibition may be useful as an adjuvant therapy in heart transplantation.
Keywords
Adenoviridae, Animals, Cytokines, Gene Expression Regulation, Gene Therapy, Gene Transfer Techniques, Genetic Vectors, Graft Rejection, Graft Survival, Heart Transplantation, Male, Rats, Rats, Inbred F344, Rats, Inbred Lew, Receptors, Interleukin-1 Type II, Recombinant Fusion Proteins, Reverse Transcriptase Polymerase Chain Reaction
Pubmed
Web of science
Open Access
Yes
Create date
29/01/2008 14:52
Last modification date
25/09/2019 7:11
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