Fugier-Vivier Isabelle J, Rezzoug Francine, Huang Yiming, Graul-Layman Amanda J, Schanie Carrie L, Xu Hong, Chilton Paula M, Ildstad Suzanne T
Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, USA.
J Exp Med. 2005 Feb 7;201(3):373-83. doi: 10.1084/jem.20041399.
Bone marrow transplantation offers great promise for treating a number of disease states. However, the widespread application of this approach is dependent upon the development of less toxic methods to establish chimerism and avoid graft-versus-host disease (GVHD). CD8+/TCR- facilitating cells (FCs) have been shown to enhance engraftment of hematopoietic stem cells (HSCs) in allogeneic recipients without causing GVHD. In the present studies, we have identified the main subpopulation of FCs as plasmacytoid precursor dendritic cells (p-preDCs). FCs and p-preDCs share many phenotypic, morphological, and functional features: both produce IFN-alpha and TNF-alpha, both are activated by toll-like receptor (TLR)-9 ligand (CpG ODN) stimulation, and both expand and mature after Flt3 ligand (FL) treatment. FL-mobilized FCs, most of which express a preDC phenotype, significantly enhance engraftment of HSCs and induce donor-specific tolerance to skin allografts. However, p-preDCs alone or p-preDCs from the FC population facilitate HSC engraftment less efficiently than total FCs. Moreover, FCs depleted of preDCs completely fail to facilitate HSC engraftment. These results are the first to define a direct functional role for p-preDCs in HSC engraftment, and also suggest that p-preDCs need to be in a certain state of maturation/activation to be fully functional.
骨髓移植为治疗多种疾病状态带来了巨大希望。然而，这种方法的广泛应用依赖于开发毒性较小的方法来建立嵌合体并避免移植物抗宿主病（GVHD）。已证明CD8 + /TCR - 促进细胞（FCs）可增强异基因受体中造血干细胞（HSCs）的植入，而不会引起GVHD。在本研究中，我们已确定FCs的主要亚群为浆细胞样前体树突状细胞（p-preDCs）。FCs和p-preDCs具有许多表型、形态和功能特征：两者均产生IFN-α和TNF-α，两者均通过Toll样受体（TLR）-9配体（CpG ODN）刺激而被激活，并且两者在Flt3配体（FL）处理后均会扩增并成熟。FL动员的FCs，其中大多数表达前体树突状细胞表型，可显著增强HSCs的植入并诱导对皮肤同种异体移植物的供体特异性耐受。然而，单独的p-preDCs或来自FC群体的p-preDCs促进HSC植入的效率低于总FCs。此外，去除前体树突状细胞的FCs完全无法促进HSC植入。这些结果首次确定了p-preDCs在HSC植入中的直接功能作用，并且还表明p-preDCs需要处于一定的成熟/激活状态才能发挥全部功能。
