Contassot E, Robinet E, Angonin R, Laithier V, Bittencourt M, Pavy J J, Cahn J Y, Hervé P, Tiberghien P
Laboratoire de Thérapeutique Immuno-moléculaire, Etablissement de Transfusion Sanguine de Franche-Comté, Besançon, France.
Bone Marrow Transplant. 1998 Dec;22(11):1097-102. doi: 10.1038/sj.bmt.1701492.
GVHD remains a major source of morbidity and mortality after non-T cell-depleted BMT. The use of donor T lymphocytes expressing a suicide gene could lead to specific immunomodulation after BMT. We are currently evaluating such an approach in a phase I clinical study. A 12-day ex vivo expansion is required to generate gene-modified donor T lymphocytes. CsA is commonly used for GVHD prophylaxis. We analyzed, in a murine GVHD model, the effects of CsA administration on the alloreactivity of fresh or ex vivo-expanded T cells. Variable amounts of fresh or ex vivo-expanded T cells were administered in conjunction with a marrow graft to lethally irradiated allogeneic mice. As expected, a protective effect of CsA with a delayed GVHD-related mortality (P < 0.01 vs saline treatment) was observed in mice receiving fresh splenocytes. However, CsA treatment had no effect (P = NS) in mice experiencing lethal GVHD induced by ex vivo-expanded T cells whether or not the T cells had been 'rested' in low-dose IL-2 prior to in vivo administration. In agreement with the in vivo findings, CsA also inhibited the in vitro proliferation of alloreactive fresh T cells while having no significant inhibitory effect on the alloreactivity of ex vivo-expanded T lymphocytes. Overall, we demonstrate that the alloreactivity of ex vivo-expanded T lymphocytes is not sensitive to CsA and that this differential effect of CsA is not related to the alloreactive potential of the infused T cells. These findings could be highly relevant when considering allogeneic T cell therapy approaches.
移植物抗宿主病（GVHD）仍然是未去除T细胞的骨髓移植（BMT）后发病和死亡的主要原因。使用表达自杀基因的供体T淋巴细胞可能会导致BMT后的特异性免疫调节。我们目前正在一项I期临床研究中评估这种方法。需要进行12天的体外扩增以产生基因修饰的供体T淋巴细胞。环孢素A（CsA）常用于预防GVHD。我们在小鼠GVHD模型中分析了给予CsA对新鲜或体外扩增的T细胞同种异体反应性的影响。将不同数量的新鲜或体外扩增的T细胞与骨髓移植一起给予接受致死性照射的同种异体小鼠。正如预期的那样，在接受新鲜脾细胞的小鼠中观察到CsA具有保护作用，且与GVHD相关的死亡率延迟（与盐水处理相比，P < 0.01）。然而，无论T细胞在体内给药前是否在低剂量白细胞介素-2中“静息”，CsA治疗对由体外扩增的T细胞诱导的致死性GVHD小鼠均无作用（P =无显著性差异）。与体内研究结果一致，CsA也抑制了同种反应性新鲜T细胞的体外增殖，而对体外扩增的T淋巴细胞的同种异体反应性没有显著抑制作用。总体而言，我们证明体外扩增的T淋巴细胞的同种异体反应性对CsA不敏感，且CsA的这种差异效应与输注的T细胞的同种异体反应潜力无关。在考虑同种异体T细胞治疗方法时，这些发现可能具有高度相关性。
