Flt3L Treatment of Bone Marrow Donors Increases Graft Plasmacytoid Dendritic Cell Content and Improves Allogeneic Transplantation Outcomes

• Type of Material: Article
• Authors: Mojibade Hassan, Emory University; Alina Ulezko, Emory University; Jian-Ming Li, Emory University; Sakura Hosoba, Emory University; Manali Rupji, Emory University; Jeanne Kowalski, Emory University; Adam J Perricone, Emory University; David Jaye, Emory University; Henry Marsh, Celldex Therapeutics, Hampton; Michael Yellin, Celldex Therapeutics, Hampton; Steven Devine, National Marrow Donor Program, Minneapolis; Edmund K Waller, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbmt.2018.11.029
• Title of Journal or Parent Work: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
• Volume: 25
• Issue: 6
• Start Page: 1075
• End Page: 1084
• Grant/Funding Information: This work was supported by the National Institutes of Health Grant 5R01-CA188523. Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource and Emory Integrated Genomics Core (EIGC) Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. This work was supported by the Research Pathology Shared Resource and the Cancer Animal Models of Winship Cancer Institute.
• Keywords: Immunology; Science & Technology; EFFICACY; CDX-301; VERSUS-HOST-DISEASE; SAFETY; Transplantation; NAIVE T-CELLS; LIGAND; Hematology; INNATE; GAMMA; Allogeneic transplantation; Life Sciences & Biomedicine; FIt3L; Plasmacytoid dendritic cells; Graft-versus-host disease; RECIPIENTS; CHEMOKINE RECEPTORS; Graft-versus-leukemia
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology; Health Sciences, Pathology

Abstract

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.