Rejection following donor or recipient preoperative treatment with FTY720 in rat small bowel transplantation.
BACKGROUND
Severe rejection of small bowel transplantation (SBTx) has been ascribed to abundant lymphoid tissues in the small intestine without well-established evidence. However, the role of donor lymphocytes in rejection is still unclear. The novel immunosuppressant, FTY720, is reported to transfer peripheral blood lymphocytes (PBLs) to lymphoid tissues such as mesenteric lymph nodes (MLNs) and Peyer patches (PP). In the present study, the number of donor lymphocytes in the graft was increased by FTY720, and the influence on rejection was studied in a rat model. Furthermore, the number of the PBL of recipient was decreased by FTY720 before SBTx and the effect on rejection was examined.


METHODS
Orthotopic total SBTx was performed in Brown-Norway and Lewis rats. In the donor pretreatment study, FTY720 was administrated to donor rats 24 h prior to harvesting to increase the number of graft lymphocytes (FTY donor-pretreated group). In contrast, MLNs were surgically removed from the grafts to decrease the number of graft lymphocytes (MLN-resected group). In the recipient pretreatment study, FTY720 was administrated to recipient rats 24 h before SBTx to decrease recipient PBL (FTY group). In contrast, a subclinical dose of cyclosporine A (CsA) was administrated after SBTx (CsA group). Rats were administrated preoperative FTY720 combined with post-SBTx CsA (FTY+CsA group). Graft survival, pathology, lymphocyte count, and subtype were examined.


RESULTS
In the donor pretreatment study, pretreatment with FTY720 did not enhance graft rejection. MLN resection did not prolong graft survival. In the recipient pretreatment study, FTY720 caused a significant reduction in the number of infiltrating lymphocytes in the graft, as well as the percentage of recipient CD4+ and CD25+ cells within the graft. FTY720 and CsA synergistically prolonged graft survival.


CONCLUSIONS
SBTx rejection correlated with the number of recipient PBL, and not with the number of donor lymphocytes transplanted together with the graft. The pretreatment of the recipient with FTY720 was effective in the case of combined use of the low-dose postoperative CsA.
Sakagawa
Taichi
T
First Department of Surgery, Ehime University School of Medicine, Shitsukawa Shigenobu-cho, Onsen-gun, 791-0295, Japan. sakagawa@pop.m.ehime-u.ac.jp
Kiyochi
Hidenori
H
Honda
Kazuo
K
Kobayashi
Nobuaki
N
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008198:Lymph Nodes / Q000276:immunology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D011292:Premedication; D011300:Preoperative Care; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives; D014019:Tissue Donors
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine