Biol Blood Marrow Transplant. 2018 Nov 29. pii: S1083-8791(18)30774-2. doi: 10.1016/j.bbmt.2018.11.029. [Epub ahead of print]
Flt3L Treatment of Bone Marrow Donors Increases Graft Plasmacytoid Dendritic Cell Content and Improves Allogeneic Transplantation Outcomes.
Hassan M1, Antonova AU1, Li JM1, Hosoba S1, Rupji M2, Kowalski J2, Perricone AJ3, Jaye DL3, Marsh H4, Yellin M4, Devine S5, Waller EK6.
1
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
2
Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, Georgia.
3
Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia.
4
Celldex Therapeutics, Hampton, New Jersey.
5
National Marrow Donor Program, Minneapolis, Minnesota.
6
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia. Electronic address: ekw72@earthlink.net.
A higher number of donor plasmacytoid dendritic cells (pDCs) is associated with increased survival and reduced graft-versus-host disease (GVHD) in human recipients of unrelated donor bone marrow (BM) grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts. We show that in murine models, donor BM pDCs are associated with increased survival and decreased GVHD compared with G-CSF-mobilized pDCs. To increase the content of pDCs in BM grafts, we studied the effect of FMS-like tyrosine kinase 3 ligand (Flt3L) treatment of murine BM donors on transplantation outcomes. Flt3L treatment (300 µg/kg/day) resulted in a schedule-dependent increase in the content of pDCs in the BM. Mice treated on days -4 and -1 had a >5-fold increase in pDC content without significant changes in numbers of HSCs, T cells, B cells, and natural killer cells in the BM graft. In an MHC-mismatched murine transplant model, recipients of Flt3L-treated T cell-depleted (TCD) BM (TCD F-BM) and cytokine-untreated T cells had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarized T cells post-transplantation compared with recipients of equivalent numbers of untreated donor TCD BM and T cells. Gene array analyses of pDCs from Flt3L-treated human and murine donors showed up-regulation of adaptive immune pathways and immunoregulatory checkpoints compared with pDCs from untreated BM donors. Transplantation of TCD F-BM plus T cells resulted in no loss of the graft-versus-leukemia (GVL) effect compared with grafts from untreated donors in 2 murine GVL models. Thus, Flt3L treatment of BM donors is a novel method for increasing the pDC content in allografts, improving survival, and decreasing GVHD without diminishing the GVL effect. |
