Reduced intensity conditioning for allogeneic hematopoietic stem-cell transplant determines the kinetics of acute graft-versus-host disease.
BACKGROUND
Preparative myeloablative conditioning regimens for allogeneic hematopoietic stem-cell transplantation (HSCT) may control malignancy and facilitate engraftment but also contribute to transplant related mortality, cytokine release, and acute graft-versus-host disease (GVHD). Reduced intensity conditioning (RIC) regimens have decreased transplant related mortality but the incidence of acute GVHD, while delayed, remains unchanged. There are currently no in vivo allogeneic models of RIC HSCT, limiting studies into the mechanism behind RIC-associated GVHD.


METHODS
We developed two RIC HSCT models that result in delayed onset GVHD (major histocompatibility complex mismatched (UBI-GFP/BL6 [H-2]-->BALB/c [H-2]) and major histocompatibility complex matched, minor histocompatibility mismatched (UBI-GFP/BL6 [H-2]-->BALB.B [H-2])) enabling the effect of RIC on chimerism, dendritic cell (DC) chimerism, and GVHD to be investigated.


RESULTS
In contrast with myeloablative conditioning, we observed that RIC-associated delayed-onset GVHD is characterized by low production of tumor necrosis factor-alpha, maintenance of host DC, phenotypic DC activation, increased T-regulatory cell numbers, and a delayed emergence of activated donor DC. Furthermore, changes to the peritransplant milieu in the recipient after RIC lead to the altered activation of DC and the induction of T-regulatory responses. Reduced intensity conditioning recipients suffer less early damage to GVHD target organs. However, as donor cells engraft, activated donor DC and rising levels of tumor necrosis factor-alpha are associated with a later onset of severe GVHD.


CONCLUSIONS
Delineating the mechanisms underlying delayed onset GVHD in RIC HSCT recipients is vital to improve the prediction of disease onset and allow more targeted interventions for acute GVHD.
Turner
Brie E
BE
Biotherapy Program, Mater Medical Research Institute, South Brisbane, Queensland, Australia.
Kambouris
Melinda E
ME
Sinfield
Laura
L
Lange
Janusz
J
Burns
Ann M
AM
Lourie
Rohan
R
Atkinson
Kerry
K
Hart
Derek N J
DN
Munster
David J
DJ
Rice
Alison M
AM
D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000601:surgery; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine