Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720
Yong-Mi Kim, … , Roderick Bronson, Megan Sykes
Yong-Mi Kim, … , Roderick Bronson, Megan Sykes
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):659-669. https://doi.org/10.1172/JCI16950.
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Article

Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

Abstract

Graft-versus-host disease (GvHD) mediated by donor T cells recognizing host alloantigens is associated with beneficial graft-versus-tumor effects in recipients of allogeneic hematopoietic cell transplants. Since leukemias and lymphomas reside largely within the lymphohematopoietic system, we have proposed that the desired graft-versus-leukemia or graft-versus-lymphoma effect can be separated from the complication of GvHD by confinement of the graft-versus-host alloresponse to the lymphohematopoietic tissues. Since the new sphingosine-1-phosphate receptor agonist immunosuppressive drug FTY720 leads to trapping of T cells in secondary lymphoid tissues, we evaluated the possibility that this drug could diminish GvHD, a disease involving epithelial target tissues, while permitting a beneficial alloresponse to take place within the lymphohematopoietic system, leading to graft-versus-lymphoma effects. We demonstrate here that FTY720 markedly reduces GvHD in a clinically relevant, haploidentical strain combination, while permitting antitumor effects against a T cell lymphoma of unshared host MHC haplotype to proceed unhindered. These results establish a potential new immunotherapeutic approach to separating graft-versus-leukemia effects from GvHD.

Authors

Yong-Mi Kim, Teviah Sachs, Wannee Asavaroengchai, Roderick Bronson, Megan Sykes

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FTY inhibits GvHD induced by a rapidly lethal dose of allogeneic spleen ...
FTY inhibits GvHD induced by a rapidly lethal dose of allogeneic spleen cells. (a) GvHD mortality. (b and c) Weight curves of the syngeneic (b) and allogeneic (c) groups. Lethally irradiated B6D2F1 mice received haplotype-mismatched C3D2F1 BMCs (5 × 106) and an increased dose of spleen cells (3 × 106), as well as H2O (filled inverted triangles; n = 10) or FTY at a dose of 3 mg/kg (filled triangles; n = 10) or 6 mg/kg (×’s; n = 7), from day –2 pre-BMT until day 29 post-BMT. FTY was given at a dose of 3 mg/kg beginning on day 0 to an additional allogeneic group until day 29 post-BMT (filled circles; n = 3), or until day 100 post-BMT (+’s; n = 4). Syngeneic control groups received 5 × 106 B6D2F1 BMCs, as well as H2O (open inverted triangles; n = 5), different doses of FTY from day –2 until day 29 (3 mg/kg, open triangles, n = 5; 6 mg/kg, asterisks, n = 5), or 3 mg/kg FTY from day 0 until day 29 (open circles; n = 5).