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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Figure 4

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FTY inhibits GvHD mortality while permitting GvL effects to be observed....
FTY inhibits GvHD mortality while permitting GvL effects to be observed. Survival curves of nonleukemic control groups (a) and leukemic groups (b) are shown. (a) Nonleukemic groups received syngeneic B6D2F1 BMCs (5 × 106) with either H2O (open inverted triangles; n = 7) or FTY (3 mg/kg/d; open circles; n = 4); or they received allogeneic haplotype-mismatched C3D2F1 BMCs (5 × 106) and spleen cells (3 × 106) with either H2O (filled squares; n = 10) or 3 mg/kg/d FTY from day 0 until day 29 post-BMT (filled triangles; n = 10). (b) Leukemic groups received 5,000 EL4 cells on day 0. Mice received 5 × 106 syngeneic B6D2F1 BMCs alone (×’s; n = 6) or with FTY (3 mg/kg/d; open diamonds; n = 6). Allogeneic groups received haplotype-mismatched C3D2F1 BMCs (5 × 106) and spleen cells (1 × 106) with either H2O (filled inverted triangles; n = 10) or FTY treatment (*; n = 10).