Protection of mouse small bowel allografts by FTY720 and costimulation blockade.
BACKGROUND
The clinical application of small bowel transplantation (SBTx) is hampered by its pronounced immunogenicity. We aimed to test the hypothesis that prolonged sequestration of lymphocytes in secondary lymphoid organs may enhance the alloprotective effect of costimulation blockade.


METHODS
For this purpose, recipients of intestinal allografts were treated with MR1, FTY720, combined FTY720 plus MR1, or were left untreated. Grafts were examined 6 and 14 days after transplantation by applying a histologic rejection score, multiparameter-immunofluorescent staining, and flow cytometry.


RESULTS
FTY720 or MR1 monotherapy did not prevent the rejection of mouse intestinal allografts, whereas combined therapy with FTY720 plus MR1 profoundly inhibited rejection at day 6 and day 14 after transplantation. In FTY720-treated mice infiltration of host lymphocytes in graft mesenteric lymph nodes, Peyer's patches, intraepithelial lymphocytes, and lamina propria lymphocytes (LPLs) was reduced on day 6. Anti-CD40L antibody improved the rejection score at day 14 but had no effect at day 6. Importantly, host CD8 T-cell infiltration in graft LPLs was significantly reduced compared with all other groups.


CONCLUSIONS
FTY720 plus MR1 effectively inhibited intestinal allograft rejection in mice, possibly by enhancing the alloprotective effects of costimulation blockade by prolonged sequestration of lymphocytes in secondary lymphoid organs.
Department of Surgery, The 1st Affiliated Hospital of Zhejiang University, Zhejiang, China.
Sheng
S
Yan
Jose-Ignacio
JI
Rodriguez-Barbosa
Oliver
O
Pabst
Jan H
JH
Beckmann
Volker
V
Brinkmann
Reinhold
R
Förster
Matthias W
MW
Hoffmann
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000187:drug effects / Q000637:transplantation*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D014184:Transplantation, Homologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine