TY - JOUR
T1 - Antisense oligodeoxynucleotides prevent acute cardiac allograft rejection via a novel, nontoxic, highly efficient transfection method
AU - Poston, Robert S.
AU - Mann, Michael J.
AU - Hoyt, E. Grant
AU - Ennen, Michael
AU - Dzau, Victor J.
AU - Robbins, Robert C.
PY - 1999/9/27
Y1 - 1999/9/27
N2 - Background. We hypothesized that ex vivo donor allograft transfection with antisense oligodeoxynucleotide (AS ODN) would inhibit the expression of intercellular adhesion molecule (ICAM)-1, an important mediator of T-cell adhesion and costimulation, and therefore suppress acute cardiac rejection. Methods. Hearts were transfected ex vivo with AS, reverse AS ODN, or saline by applying 3 atm pressure for 45 min at 4 °C. Grafts were then transplanted into allogenic recipients ± treatment with leukocyte function-associated antigen (LFA)-1 monoclonal antibody (mAb) (1.5 mg/kg intravenously), cyclosporine (2.5 mg/kg/day p.o.), or rapamycin (0.025 mg/kg/day intraperitoneally). Reperfusion injury was assessed in grafts harvested at early time points using the myeloperoxidase, %wet weight, and %contraction band necrosis assays; transfection efficiency was assessed using fluorescent microscopy; and efficacy of ICAM-1 blockade was assessed using immunohistochemistry. Other grafts were followed until rejection with donor/third-party skin grafting, adoptive transfer, and interleukin 2 infusion studies in selected recipients. Results. Transfection was highly efficient (fluorescein isothiocyanate-ODN in 48 ± 5% of total myocardial nuclei), nontoxic, and reduced the ICAM-1-positive area to 53 ± 14% versus having no effect on MHC class I expression (n = 4). The incidence of survival >60 days after AS ODN + LFA-1 monoclonal antibody was 75%, significantly higher than other regimens. Conclusion. AS ODN hyperbaric transfection proved highly efficient, effective at ICAM-1 blockade, and induced cardiac allograft tolerance when combined with LFA-1 monoclonal antibody. This highly targeted alteration of allograft immunogenicity may have an important role in future immunosuppressive strategies.
AB - Background. We hypothesized that ex vivo donor allograft transfection with antisense oligodeoxynucleotide (AS ODN) would inhibit the expression of intercellular adhesion molecule (ICAM)-1, an important mediator of T-cell adhesion and costimulation, and therefore suppress acute cardiac rejection. Methods. Hearts were transfected ex vivo with AS, reverse AS ODN, or saline by applying 3 atm pressure for 45 min at 4 °C. Grafts were then transplanted into allogenic recipients ± treatment with leukocyte function-associated antigen (LFA)-1 monoclonal antibody (mAb) (1.5 mg/kg intravenously), cyclosporine (2.5 mg/kg/day p.o.), or rapamycin (0.025 mg/kg/day intraperitoneally). Reperfusion injury was assessed in grafts harvested at early time points using the myeloperoxidase, %wet weight, and %contraction band necrosis assays; transfection efficiency was assessed using fluorescent microscopy; and efficacy of ICAM-1 blockade was assessed using immunohistochemistry. Other grafts were followed until rejection with donor/third-party skin grafting, adoptive transfer, and interleukin 2 infusion studies in selected recipients. Results. Transfection was highly efficient (fluorescein isothiocyanate-ODN in 48 ± 5% of total myocardial nuclei), nontoxic, and reduced the ICAM-1-positive area to 53 ± 14% versus having no effect on MHC class I expression (n = 4). The incidence of survival >60 days after AS ODN + LFA-1 monoclonal antibody was 75%, significantly higher than other regimens. Conclusion. AS ODN hyperbaric transfection proved highly efficient, effective at ICAM-1 blockade, and induced cardiac allograft tolerance when combined with LFA-1 monoclonal antibody. This highly targeted alteration of allograft immunogenicity may have an important role in future immunosuppressive strategies.
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U2 - 10.1097/00007890-199909270-00015
DO - 10.1097/00007890-199909270-00015
M3 - Article
C2 - 10515383
AN - SCOPUS:0033610244
SN - 0041-1337
VL - 68
SP - 825
EP - 832
JO - Transplantation
JF - Transplantation
IS - 6
ER -