Neipp M, Gammie J S, Exner B G, Li S, Chambers W H, Pham S M, Ildstad S T
Institute for Cellular Therapeutics, University of Louisville, Glenolden, PA 19036, USA.
Transplantation. 1999 Aug 15;68(3):369-78. doi: 10.1097/00007890-199908150-00008.
Mixed allogeneic bone marrow chimerism induces tolerance to solid organ grafts. Although we previously reported that partially ablative conditioning with 700 cGy of total body irradiation (TBI) is sufficient to allow for bone marrow engraftment in mice, we determined that a minimum of 1000 cGy was required in the rat. Because T cells and NK cells are critical in bone marrow graft rejection, our purpose was to examine whether targeting of radioresistant NK cells and/or T cells in the recipient hematopoietic microenvironment would reduce the TBI dose required for engraftment of allogeneic rat bone marrow.
Wistar Furth rats received either anti-NK3.2.3 monoclonal antibodies on days -3 and -2, anti-lymphocyte serum on day -5, a combination of both or no pretreatment. TBI was performed on day 0 and rats were reconstituted with 100x10(6) T cell-depleted bone marrow cells from ACI donors.
Engraftment of T cell-depleted rat bone marrow was readily achieved in animals conditioned with 1000 cGy TBI alone (12/12) and the level of donor chimerism averaged 89%. At 900 cGy TBI alone only one of eight recipients engrafted. In striking contrast, 11 of 12 animals pretreated with anti-NK monoclonal antibodies and irradiated with 900 cGy showed donor chimerism at a mean level of 41%. No further enhancement of bone marrow engraftment could be achieved when recipients were pretreated with antilymphocyte serum alone or antilymphocyte serum plus anti-NK monoclonal antibodies. Mixed allogeneic chimeras exhibited stable multilineage chimerism and donor-specific tolerance to subsequent cardiac allografts.
Specific targeting of radioresistant host NK cells allows for a significant reduction of the TBI dose required for allogeneic bone marrow engraftment.
混合异基因骨髓嵌合体可诱导对实体器官移植的耐受。尽管我们之前报道过，用700 cGy全身照射（TBI）进行部分清髓预处理足以使小鼠骨髓植入，但我们确定大鼠至少需要1000 cGy。由于T细胞和NK细胞在骨髓移植排斥中起关键作用，我们的目的是研究在受体造血微环境中靶向抗辐射的NK细胞和/或T细胞是否会降低异基因大鼠骨髓植入所需的TBI剂量。
Wistar Furth大鼠在第-3天和第-2天接受抗NK3.2.3单克隆抗体，在第-5天接受抗淋巴细胞血清，两者联合使用或不进行预处理。在第0天进行TBI，并用来自ACI供体的100×10⁶个去除T细胞的骨髓细胞对大鼠进行重建。
仅用1000 cGy TBI预处理的动物中，去除T细胞的大鼠骨髓很容易植入（12/12），供体嵌合体水平平均为89%。仅用900 cGy TBI时，8只受体中只有1只植入。与之形成鲜明对比的是，12只接受抗NK单克隆抗体预处理并接受900 cGy照射的动物中有11只显示供体嵌合体，平均水平为41%。当受体仅用抗淋巴细胞血清或抗淋巴细胞血清加抗NK单克隆抗体预处理时，骨髓植入没有进一步增强。混合异基因嵌合体表现出稳定的多谱系嵌合体以及对后续心脏同种异体移植的供体特异性耐受。
特异性靶向抗辐射的宿主NK细胞可显著降低异基因骨髓植入所需的TBI剂量。
