BLOCKING OF HEART ALLOGRAFT-REJECTION BY INTERCELLULAR-ADHESION MOLECULE-1 ANTISENSE OLIGONUCLEOTIDES ALONE OR IN COMBINATION WITH OTHER IMMUNOSUPPRESSIVE MODALITIES

Intercellular adhesion molecule-1 (ICAM-1) binds circulating leukocyte s through interactions with beta(2) integrins, LFA-1, and macrophage A g-1. The phosphorothioate antisense oligodeoxynucleotide, IP-3082, spe cific for ICAM-1 mRNA inhibited ICAM-1, but not vascular cell adhesion molecule-1, mRNA induction and expression of ICAM-1 molecules by mous e endothelioma cells. Scrambled control oligonucleotides were ineffect ive. Untreated C3H (H-2(k)) mice rejected C57BL/10 (H-2(b)) heart allo grafts with a mean survival time of 7.7 +/- 1.4 days. Administration i .v. of IP-3082 by a 7-day osmotic pump prolonged the survival of heart allografts in a dose-dependent fashion: 1.25 mg/kg, to 11 +/- 0 days; 2.5 mg/kg, to 12 +/- 2.7 days; 5 mg/kg, to 14.1 +/- 2.7 days; and 10 mg/kg, to 15.3 +/- 5.8 days (all p < 0.01). Control IP-1082 (10 mg/kg) was ineffective (7 +/- 0.8 days). Although 7-day anti-LFA-1 mAb (50 m u g/day; i.p.) prolonged allograft survival to 14.1 +/- 2.7 days, the addition of IP-3082 (5.0 mg/kg x 7 days) induced donor-specific transp lantation tolerance (>150 days). Furthermore, IP-3082 (5 mg/kg x 7 day s) acted synergistically with antilymphocyte serum, rapamycin, and bre quinar, but not cyclosporin A: a single antilymphocyte serum (0.2 ml) i.p. injection alone prolonged graft survival to 10 +/- 0.5 days (p < 0.01) and in combination with IP-3082 (5 mg/kg), to 32.2 +/- 8.3 days (p < 0.001); rapamycin (0.1 mg/kg x 7 days; i.v.) alone prolonged surv ival to 13 +/- 7.5 days (p < 0.01), and with IP-3082, to 32.4 +/- 8.9 days (p < 0.03); brequinar (0.5 mg/kg x 7 days; oral gavage) alone to 12 +/- 2.4 days (p ( 0.05), and with IP-3082 (5 mg/kg), to 38.8 +/- 30 .2 days (p < 0.01); in contrast, cyclosporin A (5 mg/kg x 7 days; i.v. ) alone produced graft survival of 9.8 +/- 1.3 days (p < 0.1 and in co mbination with IP-3082 (5 mg/kg), produced survival of 7.8 +/- 3.5 day s (NS). Thus, antisense oligonucleotides may proffer a selective gene- targeted immunosuppressive therapy for organ transplantation.