FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal.
The immunomodulator FTY720 (FTY) is beneficial in models of graft-versus-host disease, solid organ transplantation, and autoimmunity and has been approved for use in patients with multiple sclerosis. FTY modifies the homing and migration of many cell types. We report that FTY has profound positive and negative effects on allogeneic bone marrow (BM) engraftment in sublethally irradiated recipients. FTY increased donor hematopoietic progenitors in the BM, resulting in high donor engraftment in the B cell, myeloid cell, and natural killer cell, but not T cell, lineages. Donor T cell progenitors within the thymus of FTY-treated recipients were dramatically reduced, resulting in a lack of donor T cell reconstitution. In addition to preventing the ingress of donor (and host) T cell progenitors, FTY prevented the egress of fully functional host CD4+CD8- and CD4-CD8+ thymocytes that on cessation of FTY administration were able to exit from the thymus and contribute to a rapid and complete rejection of a well-established donor BM graft. When used in combination with anti-CD40L mAbs to block the CD40L:CD40 costimulatory pathway, FTY markedly enhanced anti-CD40L mAb-mediated alloengraftment promotion. In contrast to FTY alone, the combination of anti-CD40L mAb and FTY resulted in a surprisingly stable, multilineage, long-term donor chimerism. These data illustrate FTY's profound migration modulating effects and suggest a use in combinatorial therapy in achieving stable alloengraftment under nonmyeloablative conditions.
Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Patricia A
PA
Taylor
Ryan M
RM
Kelly
Nick D
ND
Bade
Michelle J
MJ
Smith
Heather E
HE
Stefanski
Bruce R
BR
Blazar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D023201:CD40 Ligand; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine