Brandau S, Böhle A, Thanhäuser A, Ernst M, Mattern T, Ulmer A J, Flad H D
Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel, Germany.
Clin Infect Dis. 2000 Sep;31 Suppl 3:S94-S100. doi: 10.1086/314068.
Tumor regression induced in cancer patients by local instillation of bacillus Calmette-Guérin (BCG) into the bladder is considered to be mediated by cellular immune and inflammatory reactions. In an attempt to elucidate which of these effects are relevant to tumoricidal activity, an in vitro system was employed in which the immunostimulatory effects of BCG could be studied. This report describes the induction of BCG-activated killer (BAK) cells, which effectively lyse bladder tumor cells. Human peripheral blood mononuclear cells (PBMC) were stimulated with viable and sonicated BCG (v-BCG and s-BCG, respectively) to generate BAK cells. Cytotoxicity of BAK cells was comparable with the cytotoxicity exerted by lymphokine-activated killer (LAK) cells generated by interferon (IFN)-gamma but did not reach the level of interleukin-2 (IL-2)-generated LAK cells. Induction of BAK cells was possible only with v-BCG and not with s-BCG. By depletion and enrichment of defined cell populations, the cytotoxic potential of BAK cells could be attributed to a population of CD8(+) and CD56(+) double-positive lymphocytes. Macrophages and CD4(+) cells were required for the induction of killing activity but had no such activity by themselves. Furthermore, the presence of IFN-gamma and IL-2 in the supernatants harvested during the generation of BAK cells was demonstrated. Monoclonal antibodies neutralizing these cytokines abolished BCG-mediated cytotoxicity. From these results, it is concluded that the known beneficial effect of local instillation of BCG on maintenance of the relapse-free state in superficial bladder cancer may be due to local generation of BAK cells.
通过向膀胱内局部注入卡介苗（BCG）诱导癌症患者肿瘤消退被认为是由细胞免疫和炎症反应介导的。为了阐明这些效应中哪些与杀瘤活性相关，采用了一种体外系统，在该系统中可以研究BCG的免疫刺激作用。本报告描述了BCG激活的杀伤（BAK）细胞的诱导，这些细胞可有效裂解膀胱肿瘤细胞。用人外周血单个核细胞（PBMC）分别用活的和超声处理的BCG（分别为v-BCG和s-BCG）刺激以产生BAK细胞。BAK细胞的细胞毒性与干扰素（IFN）-γ产生的淋巴因子激活的杀伤（LAK）细胞所发挥的细胞毒性相当，但未达到白细胞介素-2（IL-2）产生的LAK细胞的水平。仅用v-BCG而非s-BCG能够诱导BAK细胞。通过对特定细胞群体的去除和富集，BAK细胞的细胞毒性潜能可归因于一群CD8(+)和CD56(+)双阳性淋巴细胞。巨噬细胞和CD4(+)细胞是诱导杀伤活性所必需的，但它们自身没有这种活性。此外，在BAK细胞产生过程中收获的上清液中证实存在IFN-γ和IL-2。中和这些细胞因子的单克隆抗体消除了BCG介导的细胞毒性。从这些结果可以得出结论，局部注入BCG对浅表性膀胱癌维持无复发状态的已知有益作用可能是由于局部产生BAK细胞。
