Regulation of alloresponses after bone marrow transplantation using donor T cells expressing a thymidine kinase suicide gene.
Regulation of alloresponses after bone marrow transplantation using donor T cells expressing a thymidine kinase suicide gene.
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使用表达胸苷激酶自杀基因的供体 T 细胞调节骨髓移植后的同种异体反应。
DOI：
10.1080/1042819021000016041
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发表时间：
2002
影响因子：
2.6
通讯作者：
Gendelman,Maria
中科院分区：
文献类型：
--
作者：
Drobyski,WilliamR;Gendelman,Maria
供体 T 细胞在促进同种异体骨髓移植 (BMT) 后的植入方面发挥着关键作用，但也会引起移植物抗宿主病 (GVHD)。离体 T 细胞耗竭是减少 GVHD 的有效策略，但与同种异体移植和宿主免疫受损有关。使用 MHC 不匹配的小鼠模型，我们研究了一种预防 GVHD 的替代方法，即在 BMT 后使用转基因 T 细胞在体内选择性消除供体 T 细胞，其中胸苷激酶 (TK) 自杀基因靶向 T 细胞。与未治疗的小鼠相比，接受致死照射的 AKR/J (H-2 k ) 小鼠移植 TCD C57BL/6 (B6)(H-2 b ) 骨髓 (BM) 加 B6 TK + T 细胞，然后在 BMT 后用 GCV 治疗，其 GVHD 严重程度显着降低，免疫重建得到改善，这为该策略可以减轻 GVHD 提供了原理证明。为了评估GCV施用对同种异体移植的影响，将亚致死照射的AKR小鼠单独移植TCD B6 BM或与有限数量(5 2 10 5 )的B6 TK + T细胞混合。移植后 3-4 周进行测试时，对照 TCD BM 小鼠均排斥移植物。相反，超过 80% 的 GCV 治疗小鼠具有持续的供体 T 细胞植入，与未治疗动物中观察到的情况相当。值得注意的是，与未治疗的动物相比，接受 GCV 治疗的小鼠在 BMT 后早期更有可能出现混合 T 细胞嵌合，然而，几乎所有接受 GCV 治疗的小鼠在移植后 2-3 个月都进展到完成供体 T 细胞植入。植入的保存很大程度上取决于 GCV 给药时间表，并且要求 GCV 在移植后至少延迟一周。这些研究表明，将自杀基因特异性掺入供体 T 细胞是一种可行的策略，可用于在不影响同种异体移植的情况下减少 GVHD。
Donor T cells have a critical role in promoting engraftment after allogeneic bone marrow transplantation (BMT), but also cause graft versus host disease (GVHD). Ex vivo T cell depletion has been an effective strategy to reduce GVHD but has been associated with impaired alloengraftment and host immunity. Using an MHC-mismatched murine model, we have examined an alternative approach to GVHD prevention whereby donor T cells are selectively eliminated in vivo after BMT using transgenic T cells in which a thymidine kinase (TK) suicide gene is targeted to the T cell. Lethally irradiated AKR/J (H-2 k ) mice transplanted with TCD C57BL/6 (B6)(H-2 b ) bone marrow (BM) plus B6 TK + T cells and then treated with GCV post-BMT had significantly less GVHD severity and improved immune reconstitution compared to untreated mice, providing proof of principle that this strategy could mitigate GVHD. To assess the impact of GCV administration on alloengraftment, sublethally irradiated AKR mice were transplanted with TCD B6 BM alone or admixed with limiting numbers (5 2 10 5 ) of B6 TK + T cells. When tested 3-4 weeks post-transplant, control TCD BM mice all rejected their grafts. Conversely, >80% of GCV-treated mice had sustained donor T cell engraftment comparable to what was observed in untreated animals. Notably, GCV-treated mice were more likely to have mixed T cell chimerism early post-BMT than untreated animals, however, nearly all GCV-treated mice progressed to complete donor T cell engraftment by 2-3 months post-transplant. Preservation of engraftment was critically dependent upon the GCV administration schedule and required that GCV be delayed for at least one week post-transplant. These studies demonstrate that specific incorporation of a suicide gene into donor T cells is a viable strategy that can be employed to reduce GVHD without compromising alloengraftment.