Flt-3LeExpansion of recipient CD8alpha(+) dendritic cells deletes alloreactive donor T cells and represents an alternative to posttransplant cyclophosphamide for the prevention of GVHD

Markey, KA; Kuns, RD; Browne, DJ; Gartlan, KH; Robb, RJ; Martins, JP; Henden, AS; Minnie, SA; Cheong, M; Koyama, M; Smyth, MJ; Steptoe, RJ; Belz, GT; Brocker, T; Degli-Esposti, MA; Lane, SW; Hill, GR

Author(s): Markey, KA; Kuns, RD; Browne, DJ; Gartlan, KH; Robb, RJ; Martins, JP; Henden, AS; Minnie, SA; Cheong, M; Koyama, M; Smyth, MJ; Steptoe, RJ; Belz, GT; Brocker, T; Degli-Esposti, MA; Lane, SW; Hill, GR;
Details: Publication Year 2018-04-01,Volume 24,Issue #7,Page 1604-1616
Journal Title: Clinical Cancer Research
Publication Type: Journal Article
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 CD8alpha(+) 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. (c)2018 AACR.
Publisher: AACR
Research Division(s): Molecular Immunology
PubMed ID: 29367429
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-17-2148
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-06-27 09:13:26

Last Modified: 2018-06-27 09:29:26