TY - JOUR
T1 - Bendamustine with Total Body Irradiation Limits Murine Graft-versus-Host Disease in Part Through Effects on Myeloid-Derived Suppressor Cells
AU - Stokes, Jessica
AU - Hoffman, Emely A.
AU - Molina, Megan S.
AU - Eremija, Jelena
AU - Larmonier, Nicolas
AU - Zeng, Yi
AU - Katsanis, Emmanuel
N1 - Publisher Copyright:
© 2018 American Society for Blood and Marrow Transplantation
PY - 2019/3
Y1 - 2019/3
N2 - Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11b + Gr-1 high myeloid cells are increased in the blood, bone marrow, spleen, and intestines. When Gr-1 high cells are depleted before transplantation, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of granulocyte colony-stimulating factor, which promotes CD11b + Gr-1 + myeloid cell expansion, is associated with a trend toward increased survival in BEN-TBI-conditioned mice. These findings indicate a potential role of myeloid-derived suppressor cells in the mechanism by which BEN allows engraftment with reduced GVHD. BEN-TBI conditioning may present a safer alternative to CY-TBI conditioning for allogeneic HCT.
AB - Graft-versus-host disease (GVHD) remains a significant challenge in allogeneic hematopoietic cell transplantation (HCT). An underinvestigated strategy to reduce GVHD is the modification of the preparative conditioning regimen. In the present study, we aimed to evaluate GVHD associated with bendamustine (BEN) conditioning in conjunction with total body irradiation (TBI) as an alternative to the standard myeloablative regimen of cyclophosphamide (CY) and TBI. We demonstrate that BEN-TBI conditioning, although facilitating complete donor chimerism, results in significantly less GVHD compared with CY-TBI. In BEN-TBI-conditioned mice, suppressive CD11b + Gr-1 high myeloid cells are increased in the blood, bone marrow, spleen, and intestines. When Gr-1 high cells are depleted before transplantation, the beneficial effects of BEN-TBI are partially lost. Alternatively, administration of granulocyte colony-stimulating factor, which promotes CD11b + Gr-1 + myeloid cell expansion, is associated with a trend toward increased survival in BEN-TBI-conditioned mice. These findings indicate a potential role of myeloid-derived suppressor cells in the mechanism by which BEN allows engraftment with reduced GVHD. BEN-TBI conditioning may present a safer alternative to CY-TBI conditioning for allogeneic HCT.
KW - Bendamustine
KW - Graft-versus-host disease
KW - Myeloid-derived suppressor cells
UR - http://www.scopus.com/inward/record.url?scp=85056475768&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056475768&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2018.10.009
DO - 10.1016/j.bbmt.2018.10.009
M3 - Article
C2 - 30326280
AN - SCOPUS:85056475768
SN - 1083-8791
VL - 25
SP - 405
EP - 416
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 3
ER -