Control of intestinal allograft rejection by FTY720 and costimulation blockade

The clinical application of small bowel transplantation (SBTx) is hampered by its pronounced immunogenicity. In this study we examined the effects of the novel immunosuppressant FTY720 and costimulation blockade by an anti-CD40L mAb (MR-1) in a stringent mouse model of SBTx. SBTx was performed in mice with a full MHC mismatch (donors: C3H=H-2 k; recipients: C57BL/6=H-2 b). Recipients were divided into four groups: 1, untreated group; 2, MR1 monotherapy (500 μg IV on days 0, 2, 4, and 7); 3, FTY720 monotherapy (1 mg/kg body weight PO for 14 consecutive days after transplantation); 4, FTY720 plus MR1–treated group. Graft rejection grades were assessed by H&E staining. Graft mesenteric lymph nodes (MLNs), Peyer's patches (PPs), as well as intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) were analyzed by flow cytometry and three-color immunofluorescence staining. Neither FTY720 nor MR1 monotherapy was efficient in preventing the rejection of mouse intestinal allografts, whereas FTY720 plus MR1 profoundly inhibited the rejection response at the 14th posttransplant day. The infiltration of host lymphocytes was reduced in graft MLNs, PPs, IELs, and LPLs by FTY720 therapy. FTY720 plus MR1 inhibited host CD8 + T-cell infiltration in graft LPLs when compared with grafts treated with FTY720 only. Additionally, two subpopulations, CD11b +high Gr1 − and CD11b +intermediate Gr1 + cells, were decreased in FTY720-treated grafts. FTY720 plus MR1 efficiently delayed intestinal allograft rejection in a mouse model by preventing the infiltration of host lymphocytes, particularly of CD8 + cells.