Lentivirus-mediated gene transfer of small interfering RNA against the chemokine receptor CXCR3 suppresses cytokine indicators of acute graft rejection in a rat model.

Despite improvements in immunosuppressive therapy, acute rejection remains an important cause of morbidity and late graft loss in patients undergoing liver transplantation. Increasing evidence supports an important role for chemokines and their receptors in transplant immunology. An acute liver graft rejection model in rats was used to study the role of the chemokine receptor CXCR3 in acute transplant rejection after liver transplantation by lentivirus-mediated gene transfer of small interfering RNA (siRNA) against CXCR3. Using reverse transcription-polymerase chain reaction it was first shown that three lentivirus-CXCR3 siRNA vectors inhibited the in vitro expression of CXCR3 in activated T-cells bearing CXCR3. Then, it was shown that treatment of the animals with lentivirus-CXCR3 siRNA before liver transplantation reduced CXCR3 mRNA and protein, and protein levels of interleukin (IL)-2, IL-4, IL-6 and IL-10 and interferon-gamma measured as indices of acute graft rejection. Based on the results from this animal model, targeting chemokines by the use of siRNA may become a feasible option for therapy after transplantation.