ICAM-1 ANTISENSE OLIGODEOXYNUCLEOTIDES PREVENT REPERFUSION INJURY ANDENHANCE IMMEDIATE GRAFT FUNCTION IN RENAL-TRANSPLANTATION

Background. Ischemia-reperfusion injury after organ transplantation is a major cause of delayed graft function. We showed earlier that antis ense oligodesoxynucleotides (ODN) for intercellular adhesion molecule- 1 (ICAM-1) ameliorate reperfusion injury after acute ischemia. This st udy tested the hypothesis that antisense ODN for ICAM-1 prevents ische mia-reperfusion injury and facilitates immediate graft function in a r at autotransplantation model. Methods. Both kidneys were removed from male Lewis rats and re-implanted the left kidney after 30 minutes of c old ischemia time. The warm ischemia time was 60 minutes. Sham operate d, uninephrectomized animals served as controls for renal function and histology. ICAM-1 antisense ODN (5 mg/kg), reverse ODN, or saline-veh icle were administered to donor animals i.v. six hours before autotran splantation. Glomerular filtration rate (inulin clearance), and serum creatinine concentrations were measured 24 hours post-transplantation. Tubular necrosis severity was assessed by histological grading scale. ICAM-1 expression was determined by immunohistochemistry and Western blot. Results. Antisense ODN decreased ICAM-1 expression and leukocyte infiltration significantly. Antisense ODN-treated animals showed sign ificantly less tubular necrosis, than controls. Serum creatinine of an tisense ODN-treated animals (N = 6) was 0.55 +/- 0.02 mg/dl compared t o 1.92 +/- 0.07 mg/dl in reverse ODN-treated controls (N = 6; P < 0.01 ), 24 hours after transplantation. Antisense ODN-treated animals had n ormal GFR (0.93 +/- 0.07 ml/min/kidney wt) compared to sham-operated a nimals (0.95 +/- 0.09 ml/min/kidney wt), while autotransplanted animal s treated with reverse ODN or saline-vehicle were all anuric. The isch emia-reperfusion-induced up-regulation of MHC class II was totally pre vented by antisense ODN. Conclusions. ICAM-1 inhibition ameliorates is chemia-reperfusion injury and prevents delayed graft function. Antisen se ODN-treatment of donors or donor organs for ICAM-1 may be useful fo r the prevention of reperfusion injury in human renal transplantation.