Effect of FTY720 in rat small bowel transplantation: expression of mucosal addressin cell adhesion molecule-1.
OBJECTIVE
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mediates the homing of lymphocytes to gut-associated tissues (GALT). We performed a semiquantitative analysis of MAdCAM-1 expression during small bowel graft rejection in rat treated with FTY720.


METHODS
Orthotopic small bowel transplantations (SBT) were performed from BN rats to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, 7 after operations (Isograft, untreated allograft, allograft with FTY720). FTY720 was orally administered by gavage (1 mg/kg/d) to allograft models on 7 consecutive days. Cryostat sections were prepared from grafts, including Peyer's patches (PPs). Indirect immunoperoxidase staining was performed using mAbs against MAdCAM-1. The degree of vascular endothelial staining on high endothelial venules (HEV) in the PPs was graded from 1 (low levels) to 5 (high levels), and in the vessels of the lamina propia from 1 (faint), to 2 (low at the base of villi), 3 (low to the middle of villi), 4 (high to the middle of villi), to 5 (high to villi tip).


RESULTS
The graft survival was prolonged in the FTY720-treated group. MAdCAM-1 expression on HEVs in PPs was down-regulated during rejection. In contrast its expression on endothelial cells of vessels in the lamina propria was up-regulated during rejection. In the FTY720-treated groups, MAdCAM-1 expression on HEVs in PPs was up-regulated and its expression on endothelial cells of vessels in the lamina propria was down-regulated compared with untreated allograft group.


CONCLUSIONS
Alteration in MAdCAM-1 expression may be associated with the development of SB graft rejection. The vessels at the base of villi, which are associated with lymphocyte recruitment, may become sites of intestine immune reactivity during the early phase of small bowel allograft rejection. FTY720 was found to prevent the down-regulation of MAdCAM-1 expression on HEVs in PPs and the up-regulation of its expression on endothelial cells of vessels in the lamina propria 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
Fukuzawa
M
M
D000818:Animals; D000068876:Fingolimod Hydrochloride; D005786:Gene Expression Regulation; D006085:Graft Survival / Q000187:drug effects; D007136:Immunoglobulins / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000502:physiology*; D007583:Jejunum / Q000637:transplantation*; D009088:Mucoproteins / Q000235:genetics*; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000473:pathology / Q000502:physiology*; D014185:Transplantation, Isogeneic / Q000473:pathology / Q000502:physiology
D007136:Immunoglobulins; D007166:Immunosuppressive Agents; C504268:Madcam1 protein, rat; D009088:Mucoproteins; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine