Abstract
Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.
Highlights
Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic cell transplantation
As host antigen-presenting cells (APCs) are wellknown to play a significant role in GvHD pathogenesis, we hypothesized that bendamustine combined with total body irradiation (BEN+total body irradiation (TBI)) conditioning alters host dendritic cells (DCs) in a way that attenuates acute GvHD pathogenesis
To exclude the possibility that conditioned DCs may have been differentially necroptotic or apoptotic in culture, we determined viability at the beginning of culture by Trypan blue staining and performed a Propidium Iodide and Annexin V staining at the end of coculture and determined that there were no differences in viability between BEN+TBI and cyclophosphamide with TBI (CY+TBI) conditioned DCs at either timepoint
Summary
Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic cell transplantation (alloHCT). Efforts to limit GvHD have primarily focused on depleting or modulating donor T-cells through the use of prophylactic post-transplant T-cell suppressing agents. These approaches may be associated with risks of allograft rejection and reduced graft-versus-leukemia (GvL) activity [1]. Pre-transplant conditioning regimens have direct anti-cancer effects, but can influence long-term GvHD and GvL. Still, modification of these preparative chemotherapy regimens as a means to limit GvHD and enhance GvL has received little attention
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