Inhibition of donor-derived T cells trafficking into target organs by FTY720 during acute graft-versus-host disease in small bowel transplantation

Author:

Song J1,Ito T12,Matsuda C1,Miao G1,Tanemura M1,Nishida T1,Nozawa M1,Matsuda H1,Sawa Y1

Affiliation:

1. Department of Surgery (E1), Japan

2. Department of Complementary and Alternative Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

Abstract

Summary 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-F1 (WF × 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)-γ 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-γ production. These properties may offer the potential to treat ongoing GVHD in SBTx.

Publisher

Oxford University Press (OUP)

Subject

Immunology,Immunology and Allergy

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