Long-term graft acceptance in rat heart transplantation by CTLA4Ig gene transfection combined with FTY720 treatment

CTLA4Ig strongly adheres to B7 molecules on antigen-presenting cells to blo ck intracellular signal transduction via CD28 an helper T cells, which even tually inhibits immune responses. We have demonstrated that the administrat ion to recipient animals of adenoviral vectors containing CTLA4Ig gene (adC TLA4Ig) prolonged graft survival, although the gene expression diminished i n 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 th is study, we performed adCTLA4Ig transfection combined with FTY720 treatmen t in heart-grafted rats to determine if the combination could induce a mutu al 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 or ally to some of these animals at a dosage of 5 mg/kg and again on the day o f transplantation. The median graft survival period in the adCTLA4Ig-only g roup was 27 days, whereas that in the combination group was markedly prolon ged to 56 dags. Of 15 grafts, 5 survived indefinitely. In these groups we o bserved detectable levels of CTLA4Ig in the sera 49 days after grafting; th e 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 o f adCTLA4Ig, which map be related to the long-term acceptance of grafts.