ROLE OF THE CD40 AND CD95 (APO-1 FAS) ANTIGENS IN THE APOPTOSIS OF HUMAN B-CELL MALIGNANCIES/

Ligation of CD40 inhibits apoptosis and stimulates proliferation of no rmal B cells, whereas ligation of CD95 (APO-1/Fas) induces apoptosis o f activated lymphocytes. Aberrant signalling through the CD40 and CD95 antigens could thus participate in the pathogenesis of lymphoid malig nancies. 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 exam ined. CD40 was expressed by all 30 B-cell tumours, whereas CD95 was de tected 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 agonis tic CD95 monoclonal antibody (MoAb) did not augment apoptosis in any o f the unstimulated B-cell neoplasms. CD40 triggering did not consisten tly inhibit spontaneous apoptosis, but ultimately stimulated the growt h of neoplastic B cells in most cases. Furthermore, CD40 activation le d to up-regulation of the CD95 antigen in all 30 B-cell neoplasms. Lig ation of CD95 on CD40-activated tumour cells augmented apoptosis in fi ve 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 f or ALL cells or CLL cells. Bcl-2 expression by ALL and NHL cells was s ubstantially decreased after in vitro culture, whereas Bcl-2 expressio n by CLL cells was not significantly changed. However, there was no co rrelation between the level of Bcl-2 expression and sensitivity to CD9 5-mediated apoptosis. Thus, factors other than levels of CD95 and Bcl- 2 determine susceptibility of malignant B cells to apoptosis after CD9 5 triggering. CD40-activated lymphoma cells appear to be very sensitiv e to CD95-mediated apoptosis, suggesting potential strategies for trea tment of NHL. Elucidation of the mechanisms underlying resistance of A LL and CLL cells to CD95 triggering may facilitate the development of novel therapeutic approaches to these diseases as well.