Wang D, Freeman G J, Levine H, Ritz J, Robertson M J
Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Br J Haematol. 1997 May;97(2):409-17. doi: 10.1046/j.1365-2141.1997.422688.x.
Ligation of CD40 inhibits apoptosis and stimulates proliferation of normal B cells, whereas ligation of CD95 (APO-1/Fas) induces apoptosis of activated lymphocytes. Aberrant signalling through the CD40 and CD95 antigens could thus participate in the pathogenesis of lymphoid malignancies. The expression and function of CD40 and CD95 on neoplastic B cells from patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) were examined. CD40 was expressed by all 30 B-cell tumours, whereas CD95 was detected on neoplastic B cells in only one of 10 cases of ALL, two of 10 cases of CLL, and three of 10 cases of NHL. Incubation with an agonistic CD95 monoclonal antibody (MoAb) did not augment apoptosis in any of the unstimulated B-cell neoplasms. CD40 triggering did not consistently inhibit spontaneous apoptosis, but ultimately stimulated the growth of neoplastic B cells in most cases. Furthermore, CD40 activation led to up-regulation of the CD95 antigen in all 30 B-cell neoplasms. Ligation of CD95 on CD40-activated tumour cells augmented apoptosis in five of 10 ALL, three of 10 CLL, and nine of 10 NHL cases. The degree of apoptosis induced by CD95 triggering was greater for NHL cells than for ALL cells or CLL cells. Bcl-2 expression by ALL and NHL cells was substantially decreased after in vitro culture, whereas Bcl-2 expression by CLL cells was not significantly changed. However, there was no correlation between the level of Bcl-2 expression and sensitivity to CD95-mediated apoptosis. Thus, factors other than levels of CD95 and Bcl-2 determine susceptibility of malignant B cells to apoptosis after CD95 triggering. CD40-activated lymphoma cells appear to be very sensitive to CD95-mediated apoptosis, suggesting potential strategies for treatment of NHL. Elucidation of the mechanisms underlying resistance of ALL and CLL cells to CD95 triggering may facilitate the development of novel therapeutic approaches to these diseases as well.
CD40的连接可抑制正常B细胞的凋亡并刺激其增殖，而CD95（APO-1/Fas）的连接则可诱导活化淋巴细胞的凋亡。因此，通过CD40和CD95抗原的异常信号传导可能参与淋巴系统恶性肿瘤的发病机制。我们检测了急性淋巴细胞白血病（ALL）、慢性淋巴细胞白血病（CLL）和非霍奇金淋巴瘤（NHL）患者肿瘤性B细胞上CD40和CD95的表达及功能。30例B细胞肿瘤均表达CD40，而在10例ALL中仅1例、10例CLL中仅2例以及10例NHL中仅3例的肿瘤性B细胞上检测到CD95。用一种激动性CD95单克隆抗体（MoAb）孵育并未增强任何未刺激的B细胞肿瘤中的凋亡。CD40触发并不一致地抑制自发凋亡，但在大多数情况下最终刺激了肿瘤性B细胞的生长。此外，CD40激活导致所有30例B细胞肿瘤中CD95抗原上调。在CD40激活的肿瘤细胞上连接CD95可增强10例ALL中的5例、10例CLL中的3例以及10例NHL中的9例的凋亡。CD95触发诱导的凋亡程度在NHL细胞中比在ALL细胞或CLL细胞中更大。ALL和NHL细胞在体外培养后Bcl-2表达显著降低，而CLL细胞的Bcl-2表达无明显变化。然而，Bcl-2表达水平与对CD95介导的凋亡的敏感性之间无相关性。因此，除了CD9和Bcl-这些2水平之外的因素决定了恶性B细胞在CD95触发后对凋亡的易感性。CD40激活的淋巴瘤细胞似乎对CD95介导的凋亡非常敏感，这提示了治疗NHL的潜在策略。阐明ALL和CLL细胞对CD95触发的抗性机制可能也有助于开发针对这些疾病的新治疗方法。
