Long‐term Graft Acceptance in Rat Heart Transplantation by CTLA4Ig Gene Transfection Combined with FTY720 Treatment

Abstract

CTLA4Ig strongly adheres to B7 molecules on antigen-presenting cells to block intracellular signal transduction via CD28 on helper T cells, which eventually inhibits immune responses. We have demonstrated that the administration to recipient animals of adenoviral vectors containing CTLA4Ig gene (adCTLA4Ig) prolonged graft survival, although the gene expression diminished in a time-dependent manner and the grafts were finally rejected. In addition, recipient animals treated with FTY720, a new immunosuppressant, exhibited a decrease in the number of peripheral lymphocytes due to apoptosis. In this study, we performed adCTLA4Ig transfection combined with FTY720 treatment in heart-grafted rats to determine if the combination could induce a mutual effect on graft survival. The recipient animals were given injections of 1 x 10(9) plaque-forming units of adCTLA4Ig via the tail vein immediately after grafting. On the day before transplantation we administered FTY720 orally to some of these animals at a dosage of 5 mg/kg and again on the day of transplantation. The median graft survival period in the adCTLA4Ig-only group was 27 days, whereas that in the combination group was markedly prolonged to 56 days. Of 15 grafts, 5 survived indefinitely. In these groups we observed detectable levels of CTLA4Ig in the sera 49 days after grafting; the levels were always higher in the combination group than in the adCTLA4Ig-only group. As a result, this study revealed that FTY720 and adCTLA4Ig have a potent mutual effect on graft survival during rat heart transplantation. Furthermore, it is highly possible that FTY720 enhances gene expression of adCTLA4Ig, which may be related to the long-term acceptance of grafts.

Bilirubin Oxidation Provoked by Nitric Oxide Radicals Predicts the Progression of Acute Cardiac Allograft Rejection

“…Both recipient and donor rats were intubated and ventilated with 3% isoflurane using a small Harvard rodent ventilator (Harvard Apparatus, South Natick, MA). Heterotopic cardiac transplants were performed as described previously (22). Briefly, hearts were transplanted to the cervical carotid artery and jugular vein using a standard cuff technique.…”

The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

“…24 In a rat model, FTY720 given at high doses prolonged cardiac allograft survival in recipients that were transfected with CTLA4Ig. 25 Tolerance induction through BMT with cobl relies at least in part on mechanisms other than those that lead to graft prolongation through cobl without BMT. 19 Results from models without BMT are therefore not readily transferable to models involving BMT.…”