[Study the mechanisms and inducing transplantation immune tolerance of FTY720].
OBJECTIVE
To explore the operational mechanisms and potential approach to inducing transplantation immune tolerance of FTY720.


METHODS
Mouse splenocytes were incubated with FTY720, then the DNA was extracted and analyzed using gel electrophoresis. Hearts of inbred BALB/c (H-2(d)) mice were transplanted heterotopically in C57BL/6 (H-2b) mice. Recipients were randomly divided into six groups. Group-1 (n = 6) was the nil-treated control. Groups-2, 3 and 4 were given FTY720 at the dose of 3 mg.kg(-1) by oral gavage once a day with different time courses. Group-2 (n = 14) were administrated from 3 days before transplantation (day-3) to the 11th day after the transplantation (day 11); Group-3 (n = 6) from day 0 to day 14; Group-4 (n = 6) from day-3 to day 0. Group-5 (n = 5) and 6 (n = 5) were treated with Cyclosporine A (10 mg.kg(-1)) and 40-O-(2-hydroxyethyl)-rapamycin (RAD) (3 mg.kg(-1)) respectively by daily gavage from day 3 to day 11. The long survivors (> 100 d) in Group-2 were detected with their IL-4 and IFN-gamma levels and their tolerant state was challenged with second graft: the donor type skin.


RESULTS
Apoptosis changes of the mouse splenocytes incubated with FTY720 was showed by typical DNA ladders. The median survival time (MST) of Group-1 was 8 d. MST of Group-2 was 55 d and grafts in six mice survived more than 100 d. MST of Group-3 was 16.5 d. Group-4 has a MST of 14 d with one case exceeded 100 d. MST of Group-5 and 6 were 10 d and 13 d respectively. Long survivors of Group-2 can accept donor-type skin graft and the level of IL-4 in their serum is up-regulated while IFN-gamma remained stable.


CONCLUSIONS
Pretreatment of FTY720 bring about effect on the early events of transplantation immune responses. This effect might be mediated by apoptosis induction in lymphocytes using this drug. We originally designed the regime of FTY720 monotherapy, which started pre-operationally and maintained for a short period of time, and induced stable tolerance the allo-graft in mouse.
Zhang
Lei
L
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Zhu
Tong
T
Sun
Er-wei
EW
Shen
Shi-qian
SQ
Guo
Hui
H
Min
Zhi-lian
ZL
Chen
Zhong-hua
ZH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D000068876:Fingolimod Hydrochloride; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D014181:Transplantation Immunology
D000276:Adjuvants, Immunologic; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine