Gene transfer of interleukin-18-binding protein attenuates cardiac allograft rejection.
Interleukin (IL) 18 is a potent pro-inflammatory Th1 cytokine that exerts pleiotropic effector functions in both innate and acquired immune responses. Increased IL-18 production during acute rejection has been reported in experimental heart transplantation models and in kidney transplant recipients. IL-18-binding protein (IL-18BP) binds IL-18 with high affinity and neutralizes its biologic activity. We have analyzed the efficacy of an adenoviral vector expressing an IL-18BP-Ig fusion protein in a rat model of heart transplantation. IL-18BP-Ig gene transfer into Fisher (F344) rat donor hearts resulted in prolonged graft survival in Lewis recipients (15.8 +/- 1.4 days vs. 10.3 +/- 2.5 and 10.1 +/- 2.1 days with control virus and buffer solution alone, respectively; P < 0.001). Immunohistochemical analysis revealed decreased intra-graft infiltrates of monocytes/macrophages, CD4(+), CD8alpha(+) and T-cell receptor alphabeta(+) cells after IL-18BP-Ig versus mock gene transfer (P < 0.05). Real-time reverse transcriptase polymerase chain reaction analysis showed decreased cytokine transcripts for the RANTES chemokine and transforming growth factor-beta after IL-18BP-Ig gene transfer (P < 0.05). IL-18BP-Ig gene transfer attenuates inflammatory cell infiltrates and prolongs cardiac allograft survival in rats. These results suggest a contributory role for IL-18 in acute rejection. Further studies aiming at defining the therapeutic potential of IL-18BP are warranted.
Dudler
Jean
J
Department of Rheumatology, CHUV University Hospital, Lausanne, Switzerland.
Simeoni
Eleonora
E
Fleury
Sylvain
S
Li
Jianping
J
Pagnotta
Maria
M
Pascual
Manuel
M
von Segesser
Ludwig K
LK
Vassalli
Giuseppe
G
D000256:Adenoviridae; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000378:metabolism / Q000628:therapy*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D019737:Transplants; D015854:Up-Regulation
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein