Bendamustine Conditioning Induces Phenotypic and Functional Changes in Host Antigen-Presenting Cells Which May Confer Protection Against GvHD

Abstract

Abstract Background In an MHC-mismatched mouse bone marrow transplantation (BMT) model, we have found that substituting the pre-conditioning chemotherapeutic cyclophosphamide (CY) with an alternative alkylating agent, bendamustine (Ben), can significantly reduce graft-versus-host disease (GvHD) while maintaining engraftment. The mechanisms by which Ben achieves this effect are not understood, but evidence suggests that the early cellular interactions that occur in the first week after BMT can be responsible for GvHD severity later on. Objective We hypothesized that Ben may be affecting the function and/or phenotype of host antigen presenting cells (APCs) in the early post-BMT period (before complete myeloablation is achieved). Design/Method We applied a murine myeloablative MHC-mismatched model (C57BL/6 > BALB/c) to study the effect of Ben versus CY pre-conditioning in conjunction with total body irradiation (TBI) on host APCs. Specifically, we evaluated the phenotype and activation state of splenic host CD11c+ dendritic cells (DCs) on days 1, 3, and 5 following BMT. Results We found a significant increase in number and proportion of CD8a+ DCs in Ben versus CY. We also found that the Ben CD8a+ DC subset express differing levels of activation markers versus CY CD8a+ DCs. Furthermore, functional assays revealed that Ben CD11c+ DCs induce less T cell proliferation than either CY or naïve CD11c+ DCs, and that Ben CD8a+ DCs are more suppressive than either CY or naïve CD8a+ DCs. Conclusion These results suggest that pre-transplant Ben engenders phenotypic and functional changes in host CD11c+CD8a+ splenic DCs, inducing a suppressive phenotype, signifying a possible mechanism by which Ben induces protection against GvHD.