Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation.
In small bowel transplantation (SBTx), graft-versus-host disease (GVHD) is mediated by donor-derived T cells recognizing host major histocompatibility complex (MHC) alloantigens, and represents an important immunological event influencing life in experimental and clinical situations. We evaluated the possibility that a new sphingosine 1-phosphate receptor agonist, FTY720, could diminish GVHD in a rat SBTx model through traffic alteration of donor-derived T cells in target organs. Heterotopic SBTx was performed using a parent (WF)-into-F(1) (WF x ACI) rat combination. Recipient survival, body weight, histopathology, donor-derived T cell subpopulation and cytokine production were compared with untreated controls. FTY720 inhibited lethality and histopathological changes in target organs when administered at 0.5 mg/kg, possibly due to sequestration of donor-derived T cells in the intestinal graft. FTY720 caused a significant reduction in donor T cell numbers in target organs by promoting these cells to home into donor, but not recipient, secondary lymphoid tissues. FTY720 significantly decreased production of interferon (IFN)-gamma in target organs. These findings indicate that FTY720 effectively reduced recirculation of activated donor-derived T cells and recruitment to target organs in GVHD, and was also associated with down-regulated IFN-gamma production. These properties may offer the potential to treat ongoing GVHD in SBTx.
Song
J
J
Department of Surgery (E1), Osaka University Graduate School of Medicine, Osaka, Japan.
Ito
T
T
Matsuda
C
C
Miao
G
G
Tanemura
M
M
Nishida
T
T
Nozawa
M
M
Matsuda
H
H
Sawa
Y
Y
D000208:Acute Disease; D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000096:biosynthesis; D000068876:Fingolimod Hydrochloride; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008099:Liver / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011920:Rats, Inbred WF; D012867:Skin / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D018183:Transplantation Chimera
D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine