FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease.
FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graft-vs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.
Hashimoto
Daigo
D
Biopathological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Asakura
Shoji
S
Matsuoka
Ken-ichi
K
Sakoda
Yukimi
Y
Koyama
Motoko
M
Aoyama
Kazutoshi
K
Tanimoto
Mitsune
M
Teshima
Takanori
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D000068876:Fingolimod Hydrochloride; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation
D000276:Adjuvants, Immunologic; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine