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

Abstract

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. 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. 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. 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. .

Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3

“…We next sought to determine the mechanism by which BEN+TBI conditioning promotes the prevalence of cDC1s independently of the Batf3 transcription factor. The DC subset composition observed with BEN+TBI conditioning, associated with increased cDC1s compared to other DC subsets, is consistent with enhanced Flt3 signaling following administration of exogenous Flt3 Ligand (Flt3L) (24,28). We therefore sought to measure circulating levels of Flt3L to test the hypothesis that BEN achieves greater proportions of cDC1s by enhancing Flt3L signaling.…”

“…Batf3-dependent cDC1s have been linked to suppression of GvHD through activationinduced clonal deletion of allospecific donor T-cells (24) as well as superior GvL due to the specialized ability of these cells to capture, process and present tumor Ag to CD8+ T-cells (25)(26)(27). Studies using the administration of exogenous Flt3 Ligand (Flt3L) prior to transplantation have highlighted the role that host DCs, particularly host cDC1s, play in limiting GvHD (24,28). Additionally, on the various DC subsets, greater expression of the stimulatory markers CD80 and CD86 allows for stronger engagement of naïve T-cells (29)(30)(31)(32)(33)(34)(35)(36).…”

Restoring T Cell Homeostasis After Allogeneic Stem Cell Transplantation; Principal Limitations and Future Challenges

“…In contrast, the expansion of DCs by SDF-1α therapy is largely restricted to the DC1 subset and resulted in a decrease in GVHD severity ( 23 ). Host DC1 have been shown to protect against aGVHD ( 93 , 94 ). DC1 cells have an intrinsic ability to cross present antigens on MHC-I molecules and they are poor activators of CD4 + T cells ( 95 , 96 ), a property that is likely important for preventing unwanted T cell activation during homeostatic stimulation of naïve lymphocytes.…”

Conventional dendritic cells are required for the cross-presentation of leukemia-specific antigen in a model of AML relapse post-BMT

“…In the case where only leukemia-derived antigen was present, DC were required for its cross-presentation and indeed, in the absence of DC there was no difference between OT-I accumulation when compared with the non-leukemia (i.e., no antigen) controls (red bars). This suggests that where a low-abundance, leukemia-specific antigen is present, reconstituted donor DC are critical for cross-presentation of this antigen to antigen-specific donor T cells, and can lead to a net stimulatory response rather than the deletion that occurs when recipient DC present highly abundant endogenous antigens [1].…”

“…With regard to graft-versus-host (GVH) effects, it is increasingly clear that recipient-type cDC play a largely regulatory role rather than a stimulatory one (now demonstrated in both CD4 + and CD8 + T cell systems), and that non-hematopoietic antigen presentation contributes to the initiation of MHC class II-dependent GVHD [1][2][3][4]. Donor APC influence the severity of GVHD, but are inefficient at initiating disease in isolation, and make minimal contribution to GVL in systems that utilize various cell lines [5,6].…”