Yunusov Murad Y, Georges George E, Storb Rainer, Moore Peter, Hagglund Hans, Affolter Verena, Lesnikova Marina, Gass M John, Little Marie-Térèse, Loken Michael, McKenna Hilary, Storer Barry, Nash Richard A
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Transplantation. 2003 Apr 15;75(7):933-40. doi: 10.1097/01.TP.0000057831.93385.7D.
Graft-versus-host (GVH) reactions contribute to stable engraftment of allogeneic hematopoietic stem cell transplants. It was hypothesized that the in vivo expansion of recipient dendritic cells (DC) with the administration of ligand for Flt3 (FL) could promote allogeneic engraftment after reduced-intensity conditioning by enhancing the GVH effect.
FL was first administered to three nonirradiated healthy dogs for 13 days at a dosage of 100 microg/kg/day. Next, nine dogs received 4.5 Gy total-body irradiation (TBI) and unmodified marrow grafts from dog leukocyte antigen (DLA)-identical littermates without posttransplant immunosuppression. FL was administered to the recipients at a dosage of 100 microg/kg/day from day -7 until day +5.
In normal dogs, FL produced significant increases in monocytes (CD14+) and neutrophils in the peripheral blood, a marked increase in CD1c+ cells with DC-type morphology in lymph nodes, and increased alloreactivity of third-party responders to peripheral blood mononuclear cells in mixed lymphocyte reactions (P<0.001). Sustained engraftment was observed in eight of nine (89%) FL-treated dogs compared with 14 of 37 (38%) controls (P=0.02, logistic regression). All engrafted FL-treated dogs became stable complete (n=2) or mixed (n=6) hematopoietic chimeras without significant graft-versus-host disease (GVHD). Recipient chimeric dogs (n=4) were tolerant to skin transplants from their marrow donors but rejected skin grafts from unrelated dogs within 7 to 9 days (median, 8 days).
In this study, the authors showed that FL administered to recipients promotes stable engraftment of allogeneic marrow from DLA-identical littermates after 4.5 Gy TBI without significant GVHD.
移植物抗宿主（GVH）反应有助于异基因造血干细胞移植的稳定植入。据推测，通过给予Flt3（FL）配体在体内扩增受体树突状细胞（DC），可通过增强GVH效应促进减低剂量预处理后的异基因植入。
首先对3只未接受照射的健康犬以100μg/kg/天的剂量给予FL，持续13天。接下来，9只犬接受4.5Gy全身照射（TBI），并接受来自犬白细胞抗原（DLA）相同的同窝仔犬的未修饰骨髓移植，移植后不进行免疫抑制。从第-7天至第+5天，以100μg/kg/天的剂量向受体给予FL。
在正常犬中，FL使外周血中的单核细胞（CD14+）和中性粒细胞显著增加，淋巴结中具有DC形态的CD1c+细胞显著增加，并且在混合淋巴细胞反应中第三方反应者对外周血单个核细胞的同种异体反应性增加（P<0.001）。与37只对照犬中的14只（38%）相比，9只接受FL治疗的犬中有8只（89%）观察到持续植入（P=0.02，逻辑回归）。所有植入的接受FL治疗的犬均成为稳定的完全（n=2）或混合（n=6）造血嵌合体，且无明显的移植物抗宿主病（GVHD）。受体嵌合犬（n=4）对来自其骨髓供体的皮肤移植耐受，但在7至9天内（中位数为8天）排斥来自无关犬的皮肤移植。
在本研究中，作者表明向受体给予FL可促进4.5Gy TBI后来自DLA相同同窝仔犬的异基因骨髓稳定植入，且无明显GVHD。
