Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced-Intensity Allogeneic Hemopoietic Cell Transplantation.
Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood.



We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI).



The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice.



We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.
1 Westmead Institute for Medical Research, New South Wales, Australia. 2 University of Sydney, Sydney, Australia. 3 Dendritic Cell Research, ANZAC Research Institute, Sydney, Australia. 4 Sydney Medical School, University of Sydney, Sydney, Australia.
Kifah
K
Shahin
Zamil
Z
Mattar
Pablo
P
Silveira
Wei-Hsun
WH
Hsu
Linda
L
Bendall
Derek
D
Hart
Kenneth F
KF
Bradstock
D000818:Animals; D001855:Bone Marrow Diseases / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006648:Histocompatibility; D008285:Major Histocompatibility Complex; D008807:Mice, Inbred BALB C; D019653:Myeloablative Agonists / Q000008:administration & dosage; D013154:Spleen / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014916:Whole-Body Irradiation / Q000009:adverse effects
D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine