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 Z ，Lu L ，Zhang H ，Dean NM ，Fung JJ ，Qian S ... -  《MICROSURGERY》

Application of recipient-derived dendritic cells to induce donor-specific T-cell hyporesponsiveness.

Administration of donor-derived immature dendritic cells (DC) treated with NF-kappaB oligodeoxyribonucleotides (ODN) prevents allograft rejection. We attempted to explore the use of recipient-derived DC pulsed with donor antigens, in which the donor antigens were presented to host T cells via an indirect pathway (cross-priming). Expression of CD40, CD80, and CD86 on DC was significantly inhibited by treatment with NF-kappaB ODN, whereas MHC class I and II were minimally affected. Normal C3H DC pulsed with B10 antigens stimulated proliferative responses and donor-specific CTL activity in C3H T cells, both of which were, however, markedly inhibited when DC were treated with NF-kappaB ODN. This manipulation was associated with reduced IFN-gamma and increased IL-10 production in the supernate, suggesting a Th2 bias. More frequent apoptotic T cells were observed in cultures with NF-kappaB ODN DC. In contrast to administration of normal DC pulsed with donor antigens that accelerated rejection of B10 cardiac allografts (median survival time [MST] 7 days versus 10 days in no-DC treatment control, P < .05), a single injection of 2 x 10(6) NF-kappaB ODN DC significantly prolonged allograft survival (MST 50 days, P < .05 compared with no-DC treatment control). The anti-donor CTL activity in infiltrating T cells isolated from cardiac grafts in recipients that received NF-kappaB ODN DC was significantly suppressed. These data indicate that vaccination with immature DC, propagated from recipient BM is an attractive approach to induce T-cell hyporesponsiveness.

Tiao MM ，Lu L ，Tao R ，Harnaha J ，Fung JJ ，Huang LT ，Qian S ... -  《TRANSPLANTATION PROCEEDINGS》

Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus.

Tao R ，Wang L ，Chen CH ，Wang SH ，Demarco RA ，Lotze MT ，Thai NL ，Fung JJ ，Lu L ，Qian S ... -  《-》

Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival.

Liang X ，Lu L ，Chen Z ，Vickers T ，Zhang H ，Fung JJ ，Qian S ... -  《TRANSPLANTATION》

A combination of anergic cells' adoptive transfer and rapamycin therapy prolongs cardiac allograft survival in mice.

Cai Y ，Tang XD ，Zhou PJ 《SCANDINAVIAN JOURNAL OF IMMUNOLOGY》