Administration of antisense oligodeoxyribonucleotides targeting NF-kappaB prolongs allograft survival via suppression of cytotoxicity.
Presentation of alloantigens by antigen-presenting cells (APC) deficient in expression of costimulatory molecules (CM) induces alloantigen-specific hyporesponsiveness or tolerance. NF-kappaB has been shown to be a crucial transcription factor that regulates CM expression on the surface of APC. We designed an antisense phosphorothioate oligodeoxynucleotide (ODN) to specifically inhibit mRNA of mouse NF-kappaB, resulting in a deficiency in CM expression on APC that may prolong organ allograft survival. Anti-NF-kappaB ODN was delivered systemically by an osmotic pump implanted in the abdominal cavity of recipients following transplantation of vascularized heart allografts. The animals in control groups were given scrambled control ODN or were left untreated. Normal C3H (H2(k)) recipients rejected B10 (H2(b)) heart allografts at a median survival time (MST) of 15 days. A 14-day administration of 12.5 mg/kg/day anti-NF-kappaB ODN prolonged the survival of cardiac allografts to an MST of 25 days (P <0.05). In contrast, a scrambled control ODN was not effective (MST 17 days, P >0.05 compared to untreated controls). To investigate the underlying mechanisms of the immunosuppressive effect of anti-NF-kappaB ODN administration, graft infiltrating cells, spleen cells, and serum were collected from animals on day 7 posttransplant. Freshly isolated graft-infiltrating cells from anti-NF-kappaB ODN-treated recipients exhibited significantly decreased donor-specific CTL activity. Generation of CTL activity of spleen T cells from anti-NF-kappaB ODN-treated recipients was also impaired compared with untreated animals. Administration of anti-NF-kappaB ODN did not influence the titers of complement-dependent cytotoxic antibodies. These data suggest that treatment with anti-NF-kappaB ODN markedly inhibits the cellular response of allograft recipients, resulting in significant prolongation of allograft survival. Antisense ODN therapy targeting NF-kappacB may be a novel strategy for future immunosuppressive therapy.
Chen
Zongyou
Z
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, PA 15261, USA.
Lu
Lina
L
Zhang
Hong
H
Dean
Nicholas M
NM
Fung
John J
JJ
Qian
Shiguang
S
D000818:Animals; D015316:Genetic Therapy / Q000379:methods; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000187:drug effects* / Q000276:immunology; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense