title: 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.
authors.affiliation: Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohba
authors.forename: X K
authors.initials: XK
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Kita
authors.forename: S
authors.initials: S
authors.lastname: Enosawa
authors.forename: N
authors.initials: N
authors.lastname: Funeshima
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Okuyama
authors.forename: S
authors.initials: S
authors.lastname: Ogoshi
authors.forename: S
authors.initials: S
authors.lastname: Sasaguri
authors.forename: H
authors.initials: H
authors.lastname: Amemiya
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
mesh_terms: 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
chemical_list: 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