In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation.
The immunological attributes of stem cell grafts play an important role in the outcome of allogeneic stem cell transplants. Currently, ex vivo manipulation techniques such as bulk T-cell depletion or positive selection of CD34(+) cells are utilized to improve the immunological attributes of grafts and minimize the potential for graft-versus-host disease (GvHD). Here, we demonstrate a novel graft engineering technique, which utilizes the immunomodulatory drug FTY720 for in vivo depletion of naïve T (TN ) cells from donor G-CSF-mobilized grafts without ex vivo manipulation. We show that treatment of donor mice with FTY720 during mobilization depletes grafts of TN cells and prevents lethal GvHD following transplantation in a major mismatch setting. Importantly, both stem cells and NK cells are retained in the FTY720-treated grafts. FTY720 treatment does not negatively affect the engraftment potential of stem cells as demonstrated in our congenic transplants or the functionality of NK cells. In addition, potentially useful memory T cells may be retained in the graft. These findings suggest that FTY720 may be used to optimize the immunological attributes of G-CSF-mobilized grafts by removing potentially deleterious TN cells which can contribute to GvHD, and by retaining useful cells which can promote immunity in the recipient.
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Tadepally
T
Lakshmikanth
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Frank
F
Heuts
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
S S V Jagadeeswara Rao
SS
Muvva
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Robert P A
RP
Wallin
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Anna-Karin
AK
Persson
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.|Centre de Recherche en Cancerologie de Marseille, Inserm, Marseille, France.|Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.|CNRS, Marseille, France.
Cyril
C
Fauriat
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Steven E
SE
Applequist
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Hans-Gustaf
HG
Ljunggren
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Petter
P
Höglund
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Klas
K
Kärre
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Mattias
M
Svensson
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Julius G
JG
Juarez
D000818:Animals; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005818:Genetic Engineering / Q000379:methods; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
D016179:Granulocyte Colony-Stimulating Factor; D000068876:Fingolimod Hydrochloride
Allogeneic stem cell transplantation; Graft engineering; Graft-versus-host disease; Stem cell mobilization; T cells