Effect of FTY720 in rat small bowel transplantation: apoptosis of crypt cells and lymphocytes in gut-associated lymphoid tissues.
OBJECTIVE
We investigated the extent of apoptosis in crypt cells and Peyer's patches (PPs) during small bowel allograft rejection in rats to examine the effect of FTY720 during rejection.


METHODS
Orthotopic small bowel transplantations (SBTs) were performed from BN to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, and 7 after operation: isograft, untreated allograft, allograft with FTY720. FTY720 was orally administered by gavage (1 mg/kg/d) to allograft recipients on 7 consecutive days. Cryostat sections were prepared from grafts, including PPs. An in situ end-labeling (ISEL) technique was used to detect apoptotic cells. Indirect immunoperoxidase staining was also performed using monoclonal antibodies against rat Fas/Fas-L.


RESULTS
Graft survival was prolonged in the FTY720-treated group. The number of ISEL-positive enterocytes in the allografts increased significantly on days 3, 5, and 7 compared with the isograft group. In the FTY720-treated group, the number of ISEL-positive enterocytes in the allografts was down-regulated significantly on days 3, 5, and 7 compared with untreated allograft group. In the PPs, the number of ISEL-positive mononuclear cells increased significantly in the allografts compared with the isograft group. In the FTY720-treated groups, the number of ISEL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group. The number of Fas/FasL-positive enterocytes were increased significantly in allografts compared with isograft group. In FTY720-treated groups, the number of Fas/FasL-positive enterocytes were down-regulated significantly on day 7 compared with the untreated allograft group. In the PPs, Fas/FasL-positive mononuclear cells also increased significantly on day 7 in the allografts compared with isografts. In the FTY720-treated groups, Fas/FasL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group.


CONCLUSIONS
The number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes increased during small bowel graft rejection. FTY720 prevented up-regulation of the number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes while also prolonging small bowel allograft survival.
Sugito
K
K
Nihon University, Pediatric Surgery, Tokyo, Japan. ksugito@hotmail.com
Koshinaga
T
T
Inoue
M
M
Ikeda
T
T
Hagiwara
N
N
Kusafuka
T
T
Fukuzawa
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053222:Fas Ligand Protein / Q000032:analysis; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D007421:Intestine, Small / Q000473:pathology / Q000637:transplantation*; D023421:Models, Animal; D010581:Peyer's Patches / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000473:pathology; D014185:Transplantation, Isogeneic / Q000473:pathology
D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine