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Markey, Kate A.; Kuns, Rachel D.; Browne, Daniel J.; Gartlan, Kate H.; Robb, Renee J.; Martins, J. Paulo; Henden, Andrea S.; Minnie, Simone A.; Cheong, Melody; Koyama, Motoko; Smyth, Mark J.; Steptoe, Raymond J.; Belz, Gabrielle T.; Brocker, Thomas; Degli-Esposti, Mariapia A.; Lane, Steven W.; Hill, Geoffrey R. (2018): Flt-3L Expansion of Recipient CD8(alpha+) Dendritic Cells Deletes Alloreactive Donor T Cells and Represents an Alternative to Posttransplant Cyclophosphamide for the Prevention of GVHD. In: Clinical Cancer Research, Vol. 24, No. 7: pp. 1604-1616
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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 CD8(+) 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.