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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation / methods
  • CD8 Antigens / immunology*
  • Cyclophosphamide / pharmacology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Female
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Graft vs Leukemia Effect / drug effects
  • Graft vs Leukemia Effect / immunology*
  • Leukemia / immunology
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Tissue Donors
  • Transplantation, Homologous / methods

Substances

  • CD8 Antigens
  • CD8alpha antigen
  • Membrane Proteins
  • flt3 ligand protein
  • Cyclophosphamide