Background We have previously shown that phosphorothioate intercellular adh
esion molecule (ICAM)-1 antisense oligodeoxynucleotide (oligo) IP-9125 bloc
ks the expression of rat ICARS-1 mRNA in rat L2 cells. A single ex situ per
fusion of grafts with unformulated IP-9125, suspended in Euro-Collins solut
ion, prolonged the survival of kidney allografts in fats. The present exper
iments examined whether perfusion of kidneys with unformulated IP-9125 prev
ents ischemic/reperfusion injury
Methods. Kidneys were perfused ex situ with 2 mi of Euro-Collins solution w
ithout or with IP-9125 and exposed to 30-min cold (4 degrees C storage time
) and 30-min warm (anastomosis time) ischemia, Kidneys were then transplant
ed to syngeneic nephrectomized recipients,
Results. Within 24 hr after transplantation, the glomerular filtration rate
values were reduced by almost 60% to 0.49+/-0.14 ml/min from 1.20+/-0.27 m
l/min in normal kidneys (P<0.001). Kidney perfusion with 10 mg of either IP
-12140 (0.41+/-0.07 ml/min) or IP-13944 (0.47+/-0.07 ml/min) control oligo
was ineffective. In contrast, perfusion with 10 mg of IP-9125 significantly
improved kidney function (0.8+/-0.18 ml/min; P<0.005), whereas the lower d
oses of 2 mg (0.47+/-0.13 ml/min; NS) or 4 mg (0.54+/-0.01 ml/min; NS) had
no significant effect. The glomerular filtration rate results were confirme
d by measurements of blood creatinine (CR) levels at 24 hr after grafting:
untreated recipients had a twofold higher CR value (0.10+/-0.14 mg/dl) comp
ared with normal controls (0.65+/-0.07 mg/dl; P<0,001). Although perfusion
with 10 mg of control IP-12140 (0.80+/-0.14 mg/dl) or IP-13944 (0.65+/-0.07
mg/dl) did not affect CR levels, perfusion with 10 mg of TP-9125 (0.45+/-0
.07 mg/dl) lowered CR levels. The Western blots or reverse transcription-po
lymerase chain reaction experiments performed in kidney transplants within
24 hr after grafting showed that 10 mg of TP-9125 (but not control IP-12140
) reduced the expression of ICAM-1 protein and ICAM-1 mRNA, respectively.
Conclusions. Perfusion of grafts with unformulated ICAM-1 antisense oligo s
pecifically reduces intragraft ICAM-1 protein expression and prevents ische
mic/reperfusion injury.