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 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.
Ohba
M
M
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan.
Li
X K
XK
Kita
Y
Y
Enosawa
S
S
Funeshima
N
N
Nagai
H
H
Zhang
H
H
Okuyama
T
T
Ogoshi
S
S
Sasaguri
S
S
Amemiya
H
H
Suzuki
S
S
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000235:genetics*; D060908:CTLA-4 Antigen; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000235:genetics*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics*; D013110:Sphingosine / Q000031:analogs & derivatives; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine