title: 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.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Teviah
authors.initials: T
authors.lastname: Sachs
authors.forename: Wannee
authors.initials: W
authors.lastname: Asavaroengchai
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020350:Graft vs Tumor Effect / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine