Shahin Kifah, Mattar Zamil, Silveira Pablo, Hsu Wei-Hsun, Bendall Linda, Hart Derek, Bradstock Kenneth F
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.
Transplantation. 2017 Nov;101(11):2695-2704. doi: 10.1097/TP.0000000000001733.
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.
目前大多数临床异基因造血细胞移植（alloHCT）采用减低强度预处理（RIC）而非清髓性预处理（MAC）；然而，这种治疗背后的生物学机制仍未完全明确。
我们研究了一种主要组织相容性复合体匹配、多个次要组织相容性抗原不匹配的alloHCT小鼠模型，使用来自B6（H-2）供体小鼠的骨髓（BM）细胞和脾细胞，在接受RIC后移植到BALB.B（H-2）受体小鼠体内，RIC方案为每天100mg/kg氟达拉滨，共5天，每天60mg/kg环磷酰胺，共2天，以及全身照射（TBI）。
在这种小鼠品系组合中，能够实现完全供体嵌合的最低TBI剂量为单次325cGy。与接受MAC移植的受体（850cGy的TBI加每天60mg/kg环磷酰胺，共2天）相比，接受RIC的小鼠移植物抗宿主病（GVHD）的发生率降低且发病延迟，生存期显著延长。与同基因对照相比，患有GVHD的RIC小鼠表现出骨髓抑制的迹象，有贫血、骨髓细胞减少，并显示与骨内膜骨髓龛损伤相关的骨髓B细胞淋巴细胞生成显著减少。这与RIC小鼠骨髓CD8效应T细胞增加以及血液和骨髓中辅助性T细胞1细胞因子的血浆水平升高有关。脾细胞剂量增加导致RIC小鼠GVHD发生率增加。
我们证明，在一个信息丰富的、与临床相关的RIC小鼠主要组织相容性复合体匹配的alloHCT模型中，骨髓是GVHD的主要靶器官，这一过程似乎由CD8效应T细胞驱动。
