Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients
Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients
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DOI：
10.1182/blood-2006-05-022772
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发表时间：
2007-02-01
期刊：
影响因子：
20.3
通讯作者：
Blazarl, Bruce R.
中科院分区：
文献类型：
--
作者：
Taylor, Patricia A.;Ehrhardt, Michael J.;Blazarl, Bruce R.
多次输血的个体发生骨髓排斥的风险更高。我们发现，而allosensitization导致在启动的细胞和体液免疫，预制抗体的主要障碍植入。交叉反应性同种抗体的产生导致不同MHC不同菌株的BM排斥。成像研究表明，在致敏受体中抗体介导的排斥反应非常迅速（< 3小时），而在非致敏小鼠中T细胞介导的排斥反应需要6天以上。抗体介导的BM排斥不是由于BM归巢缺陷，因为尽管直接骨髓内输注供体BM，仍发生排斥。排斥反应依赖于宿主FcR（+）细胞。骨髓细胞孵育血清从引发小鼠被淘汰在nonprimed收件人，表明持续暴露于高滴度抗体是不是必不可少的排斥反应。通过巨骨髓细胞剂量、体内T细胞耗竭和高剂量免疫球蛋白输注，在一定比例的致敏小鼠中实现了高供体植入。在该方案中增加脾切除术仅适度增加了该联合策略的疗效。这些数据证明了宿主FcR（+）细胞和宿主前体T细胞的快速同种抗体介导的BM消除，并提出了克服致敏个体植入障碍的实用策略。
Multiply-transfused individuals are at higher risk for BM rejection. We show that whereas allosensitization resulted in the priming of both cellular and humoral immunity, preformed antibody was the major barrier to engraftment. The generation of cross-reactive alloantibody led to rejection of BM of a different MHC-disparate strain. Imaging studies indicated that antibody-mediated rejection was very rapid (< 3 hours) in primed recipients, while T-cell-mediated rejection in nonprimed mice took more than 6 days. Antibody-mediated BM rejection was not due to a defect in BM homing as rejection occurred despite direct intra-BM infusion of donor BM. Rejection was dependent upon host FcR(+) cells. BM cells incubated with serum from primed mice were eliminated in nonprimed recipients, indicating that persistent exposure to high-titer antibody was not essential for rejection. High donor engraftment was achieved in a proportion of primed mice by mega-BM cell dose, in vivo T-cell depletion, and high-dose immunoglobulin infusion. The addition of splenectomy to this protocol only modestly added to the efficacy of this combination strategy. These data demonstrate both rapid alloantibody-mediated elimination of BM by host FcR(+) cells and priming of host anticionor T cells and suggest a practical strategy to overcome engraftment barriers in primed individuals.