Delain M, Tiberghien P, Racadot E, Billot M, Pariset J, Chabod J, Cahn J Y, Hervé P
Centre Régional de Transfusion Sanguine, Besançon, France.
Leukemia. 1994 Apr;8(4):642-7.
Clinical and experimental data suggest a role for the immune response in preventing leukemic relapses after allogeneic bone marrow transplantation (BMT): the graft-versus-leukemia (GVL) effect. In this report, we have evaluated the response of normal donor lymphocytes against allogeneic leukemic cells as an in vitro model of the GVL effect. We used a limiting dilution technique in order to determine the frequency of cytotoxic T-lymphocyte precursors (pre-CTL) against allogeneic leukemic blasts among normal donor lymphocytes. We demonstrate a considerable variability of CTL precursor frequency. This variability depended on leukemic populations since, for a given leukemia, the pre-CTL frequency was comparable among our tested normal allogeneic donors. Moreover, when HLA-DR negative leukemias were used as allostimulators, the pre-CTL frequencies were extremely low. In order to verify the impact of leukemic DR expression on the stimulatory capacity of leukemic cells, we selected and analyzed in mixed lymphocyte tumor cell culture (MLTC), a panel of myelogenous and lymphoblastic leukemias with variable levels of DR expression, each against different allogeneic responders. Our results demonstrated a close correlation (r = 0.953, p < 0.0001) between the proliferative response of alloactivated lymphocytes and the percentage of stimulatory leukemic cells expressing HLA-DR molecules. Anti-MHC class II monoclonal antibodies inhibited the lymphocyte proliferation in the MLTC, confirming the preponderant role of DR in the generation of this response. Overall, our results demonstrate the extreme variability of leukemic cells in their allostimulatory capacity and the central role of DR expression in determining leukemic allo-recognition. In the setting of a clinical protocol, our data suggest that the infusion of allogeneic T lymphocytes in a DR negative leukemia will not lead to an alloreactive T-cell anti-tumor effect.
临床和实验数据表明，免疫反应在异基因骨髓移植（BMT）后预防白血病复发中发挥作用：移植物抗白血病（GVL）效应。在本报告中，我们评估了正常供体淋巴细胞对异基因白血病细胞的反应，以此作为GVL效应的体外模型。我们采用有限稀释技术来确定正常供体淋巴细胞中针对异基因白血病原始细胞的细胞毒性T淋巴细胞前体（pre-CTL）频率。我们证明了CTL前体频率存在相当大的变异性。这种变异性取决于白血病群体，因为对于给定的白血病，我们测试的正常异基因供体中的pre-CTL频率相当。此外，当使用HLA-DR阴性白血病作为异源刺激物时，pre-CTL频率极低。为了验证白血病DR表达对白血病细胞刺激能力的影响，我们在混合淋巴细胞肿瘤细胞培养（MLTC）中选择并分析了一组DR表达水平不同的髓性和淋巴细胞性白血病，每种白血病针对不同的异基因反应者。我们的结果表明，同种异体激活的淋巴细胞的增殖反应与表达HLA-DR分子的刺激白血病细胞百分比之间存在密切相关性（r = 0.953，p < 0.0001）。抗MHC II类单克隆抗体抑制了MLTC中的淋巴细胞增殖，证实了DR在该反应产生中的主要作用。总体而言，我们的结果表明白血病细胞的异源刺激能力存在极大变异性，且DR表达在决定白血病同种异体识别中起核心作用。在临床方案的背景下，我们的数据表明，在DR阴性白血病中输注异基因T淋巴细胞不会导致同种异体反应性T细胞抗肿瘤效应。
