Regulation of donor T cells in the tolerant rats to graft-versus-host disease by FTY720 following small bowel transplantation.
OBJECTIVE
The potency of immunosuppression is a critical factor in small bowel transplantation (SBTx). FTY720 altered lymphocyte trafficking and prevented the donor T cells from migrating into target organs, resulting in the prolongation of recipient survival in acute graft-versus-host disease (GVHD) of SBTx. However, the effect of FTY720 on donor T cells in the chronic phase of GVHD following SBTx remains unclear.


METHODS
Heterotopic SBTx was performed in a WF-to-F1 (WF x ACI) rat combination. Recipients were given FTY720 for 14 days after SBTx. The subpopulations of donor-derived T cells and the cytokine production in the target tissues were evaluated on postoperative day 150.


RESULTS
FTY720 treatment significantly prolonged recipient survival over 150 days without any clinical signs of GVHD. The numbers of donor-derived CD4+ and CD8+ T cells in the peripheral blood, mesenteric lymph nodes, and Peyer's patches of recipients were maintained at low levels on postoperative 150, which were almost similar to the levels on postoperative day 14. In the host lamina propria, however, a significant higher number of donor T cells (CD4+, 18.4 +/- 4.3 x 10(4); CD8+, 13.9 +/- 3.6 x 10(4)) were still observed on postoperative day 150. Production of interferon-gamma was significantly reduced in target tissues by FTY720 treatment both in the acute and chronic phase. However, interleukin-4 and interleukin-10 production, which was significantly higher on day 14, returned to the level of naive rats in the chronic phase.


CONCLUSIONS
A 14-day treatment of FTY720 induced tolerance in our SBTx model. Down-regulation of both Th1 and Th2 immune response was observed in the chronic phase.
Song
J
J
Department of Surgery (E1) Osaka University Graduate School of Medicine, Osaka, Japan.
Ito
T
T
Matsuda
C
C
Tanemura
M
M
Nishida
T
T
Nozawa
M
M
Sawa
Y
Y
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D000068876:Fingolimod Hydrochloride; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000637:transplantation*; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine