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Clin Cancer Res. 2018 Apr 1;24(7):1604-1616. doi: 10.1158/1078-0432.CCR-17-2148. Epub 2018 Jan 24.

Flt-3L Expansion of Recipient CD8α+ Dendritic Cells Deletes Alloreactive Donor T Cells and Represents an Alternative to Posttransplant Cyclophosphamide for the Prevention of GVHD.

Author information

1
QIMR Berghofer Medical Research Institute, Brisbane, Australia. Kate.markey@qimr.edu.au.
2
Royal Brisbane and Women's Hospital, Brisbane, Australia.
3
School of Medicine, University of Queensland, Herston, Queensland, Australia.
4
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
5
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
6
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
7
Institute for Immunology, Ludwig-Maximilians Universitat, Munich, Germany.
8
Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia.
9
Immunology and Virology Program, Centre for Ophthalmology and Visual Science, University of Western Australia, Crawley, Western Australia.

Abstract

Purpose: Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunologic graft-versus-leukemia (GVL) effects. In practice, this must be balanced against life threatening pathology induced by graft-versus-host disease (GVHD). Recipient dendritic cells (DC) are thought to be important in the induction of GVL and GVHD.Experimental Design: We have utilized preclinical models of allogeneic BMT to dissect the role and modulation of recipient DCs in controlling donor T-cell-mediated GVHD and GVL.Results: We demonstrate that recipient CD8α+ DCs promote activation-induced clonal deletion of allospecific donor T cells after BMT. We compared pretransplant fms-like tyrosine kinase-3 ligand (Flt-3L) treatment to the current clinical strategy of posttransplant cyclophosphamide (PT-Cy) therapy. Our results demonstrate superior protection from GVHD with the immunomodulatory Flt-3L approach, and similar attenuation of GVL responses with both strategies. Strikingly, Flt-3L treatment permitted maintenance of the donor polyclonal T-cell pool, where PT-Cy did not.Conclusions: These data highlight pre-transplant Flt-3L therapy as a potent new therapeutic strategy to delete alloreactive T cells and prevent GVHD, which appears particularly well suited to haploidentical BMT where the control of infection and the prevention of GVHD are paramount. Clin Cancer Res; 24(7); 1604-16. ©2018 AACR.

PMID:
29367429
DOI:
10.1158/1078-0432.CCR-17-2148
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