Uckun F M, Gajl-Peczalska K, Myers D E, Jaszcz W, Haissig S, Ledbetter J A
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Health Sciences Center, Minneapolis 55455.
Blood. 1990 Dec 15;76(12):2449-56.
Detailed immunophenotypic analyses of immunologically classified leukemias and lymphomas showed that CD40 displays an exquisite B-lineage specificity within the human lymphopoietic system. Notably, 82% of B-lineage chronic lymphocytic leukemias (CLLs), 82% of B-lineage hairy cell leukemias (HCLs), 86% of B-lineage non-Hodgkin's lymphomas (NHLs), and 29% of B-lineage acute lymphoblastic leukemias (ALLs) were CD40+. Quantitative analyses of the correlated expression of CD40 and other B-lineage differentiation antigens on fetal lymphoid precursor cells by multiparameter two-color/three-color flow cytometry, combined with analyses of sequential antigen expression on fluorescence-activated cell fluorescence activated cell sorter (FACS) isolated immunologically distinct fetal B-cell precursor subpopulations during in vitro proliferation and differentiation, provided evidence that the acquisition of CD40 antigen in human B-cell ontogeny occurs subsequent to the expression of CD10 and CD19 antigens but before the surface expression of CD20, CD21, CD22, CD24, and surface immunoglobulin M (sIgM). Some leukemic pro-B cells from ALL patients as well as normal pro-B cell clones from fetal livers displaying germline Ig heavy chain genes were CD40+, indicating that the acquisition of CD40 antigen likely precedes the rearrangement of Ig heavy chain genes. CD40+ FACS-sorted malignant cells from B-lineage ALL as well as B-lineage NHL patients were capable of in vitro clonogenic growth, indicating the CD40 antigen is expressed on clonogenic leukemia and lymphoma cells. This hypothesis was confirmed by the ability of an anti-CD40 immunotoxin that we used as an antigen-specific cytotoxic probe to effectively kill clonogenic B-lineage ALL and NHL cells.
对免疫分类的白血病和淋巴瘤进行的详细免疫表型分析表明，CD40在人类淋巴细胞生成系统中显示出精细的B细胞谱系特异性。值得注意的是，82%的B细胞谱系慢性淋巴细胞白血病（CLL）、82%的B细胞谱系毛细胞白血病（HCL）、86%的B细胞谱系非霍奇金淋巴瘤（NHL）以及29%的B细胞谱系急性淋巴细胞白血病（ALL）为CD40阳性。通过多参数双色/三色流式细胞术对胎儿淋巴前体细胞上CD40与其他B细胞谱系分化抗原的相关表达进行定量分析，结合对荧光激活细胞荧光激活细胞分选仪（FACS）分离的免疫学上不同的胎儿B细胞前体亚群在体外增殖和分化过程中抗原表达顺序的分析，提供了证据表明，在人类B细胞个体发育中，CD40抗原的获得发生在CD10和CD19抗原表达之后，但在CD20、CD21、CD22、CD24和表面免疫球蛋白M（sIgM）的表面表达之前。一些来自ALL患者的白血病前B细胞以及来自胎儿肝脏显示种系Ig重链基因的正常前B细胞克隆为CD40阳性，这表明CD40抗原的获得可能先于Ig重链基因的重排。来自B细胞谱系ALL以及B细胞谱系NHL患者的CD40+ FACS分选的恶性细胞能够在体外进行克隆生长，表明CD40抗原在克隆性白血病和淋巴瘤细胞上表达。我们用作抗原特异性细胞毒性探针的抗CD40免疫毒素能够有效杀死克隆性B细胞谱系ALL和NHL细胞这一能力证实了这一假设。
