Tiberghien P
Laboratoire de Thérapeutique Immuno-moléculaire, Etablissement de Transfusion Sanguine de Franche-Comté, Besançon.
Transfus Clin Biol. 1997;4(3):275-80. doi: 10.1016/s1246-7820(97)80052-3.
While effectively preventing graft-versus-host disease (GVHD), ex vivo T-lymphocyte depletion of the graft unfortunately increases graft rejection and reduces the graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. The ex vivo transfer of the herpes-simplex thymidine-kinase (HS-tk) suicide gene into T-cells before their infusion with the hematopoietic stem cells, should allow for selective in vivo depletion of these T-cells with ganciclovir (GCV), if subsequent GVHD was to occur. We have demonstrated that retroviral-mediated transfer of HS-tk and Neomycine resistance genes in T-lymphocytes, followed by G418 selection, results in T-cells specifically inhibited by GCV with no bystander effect. In a phase I study, escalating amounts of HS-tk expressing T-cells are infused in conjunction with a T-cell depleted marrow graft to allogeneic HLA identical recipients. Toxicity, survival alloreactivity and GCV-sensitivity of the gene-modified cells are monitored.
在有效预防移植物抗宿主病（GVHD）的同时，不幸的是，移植物的体外T淋巴细胞清除会增加移植物排斥反应，并降低异基因造血干细胞移植后的移植物抗白血病（GVL）效应。在将T细胞与造血干细胞一起输注之前，将单纯疱疹胸苷激酶（HS-tk）自杀基因体外转移到T细胞中，如果随后发生GVHD，应该可以用更昔洛韦（GCV）在体内选择性清除这些T细胞。我们已经证明，逆转录病毒介导的HS-tk和新霉素抗性基因在T淋巴细胞中的转移，随后进行G418筛选，会导致T细胞被GCV特异性抑制，且无旁观者效应。在一项I期研究中，将递增数量的表达HS-tk的T细胞与T细胞清除的骨髓移植物一起输注给同基因HLA相同的异基因受体。监测基因修饰细胞的毒性、存活同种异体反应性和GCV敏感性。
