Ophir Eran, Reisner Yair
Weizmann Institute of Science, Department of Immunology, Rehovot 76100, Israel.
Int Immunopharmacol. 2009 Jun;9(6):694-700. doi: 10.1016/j.intimp.2008.12.009. Epub 2009 Jan 16.
The use of hematopoietic stem cell transplantation (HSCT) for the establishment of mixed chimerism represents a viable and attractive approach for generating tolerance in transplantation biology, as it generally leads to durable immune tolerance, enabling the subsequent engraftment of organ transplants without the need for a deleterious continuous immunosuppressive therapy. However, in order to apply HSCT to patients in a manner that enables long term survival, transplant-related mortality must be minimized by eliminating the risk for graft-versus-host-disease (GVHD) and by reducing the toxicity of the conditioning protocol. T-cell depleted bone marrow transplants (TDBMT) have been shown to adequately eliminate GVHD. However, even in leukemia patients undergoing supralethal conditioning, mismatched TDBMT are vigorously rejected. This barrier can be overcome through the modulatory activity of CD34 cells, which are endowed with veto activity, by the use of megadose stem cell transplants. In mice, megadoses of Sca+lin-hematopoietic stem cells can induce mixed chimerism following sub-lethal conditioning. Nevertheless, the number of human CD34 cells that can be harvested is not likely to be sufficient to overcome rejection under reduced intensity conditioning (RIC), which might be acceptable in recipients of organ transplantation. To address this challenge, we investigated a novel source of veto cells, namely anti 3rd-party cytotoxic T cells (CTLs) which are depleted of GVH reactivity, combined with megadoses of purified stem cells and a RIC protocol. This approach might provide a safer modality for the induction of durable chimerism.
利用造血干细胞移植（HSCT）建立混合嵌合体是移植生物学中产生免疫耐受的一种可行且有吸引力的方法，因为它通常能导致持久的免疫耐受，使随后的器官移植得以植入，而无需有害的持续免疫抑制治疗。然而，为了以能实现长期生存的方式将HSCT应用于患者，必须通过消除移植物抗宿主病（GVHD）风险和降低预处理方案的毒性来将移植相关死亡率降至最低。已证明去除T细胞的骨髓移植（TDBMT）能充分消除GVHD。然而，即使在接受超致死剂量预处理的白血病患者中，不匹配的TDBMT也会被强烈排斥。通过使用大剂量干细胞移植，利用具有否决活性的CD34细胞的调节活性可克服这一障碍。在小鼠中，亚致死剂量预处理后，大剂量的Sca+lin-造血干细胞可诱导混合嵌合体。然而，在强度降低的预处理（RIC）下，收获的人类CD34细胞数量可能不足以克服排斥反应，而RIC在器官移植受者中可能是可接受的。为应对这一挑战，我们研究了一种新型否决细胞来源，即去除GVH反应性的抗第三方细胞毒性T细胞（CTL），并结合大剂量纯化干细胞和RIC方案。这种方法可能为诱导持久嵌合体提供一种更安全的方式。
