Inhibition of human B-cell lymphoma growth by CD40 stimulation

Funakoshi, Satoshi; Longo, Dan L.; Beckwith, Margaret; Conley, Denise K.; Tsarfaty, Galia; Tsarfaty, IIan; Armitage, Richard J.; Fanslow, William C.; Spriggs, Melanie K.; Murphy, William J.

doi:10.1182/blood.v83.10.2787.2787

Cited by 203 publications

(59 citation statements)

References 22 publications

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“…In contrast to its anti-apoptotic function on normal B cells, CD40 can trigger apoptosis of cell lines derived from transformed B cells or epithelial cells (Funakoshi et al, 1994;Hess & Engelmann, 1996). Ligation of CD40 appeared to augment apoptosis in two NHL samples that we tested; in the remaining three samples no significant effect on spontaneous apoptosis was observed.…”

Section: Discussionmentioning

confidence: 67%

Role of the CD40 and CD95 (APO‐1/Fas) antigens in the apoptosis of human B‐cell malignancies

et al. 1997

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Summary. 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.

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Section: Discussionmentioning

confidence: 67%

Role of the CD40 and CD95 (APO‐1/Fas) antigens in the apoptosis of human B‐cell malignancies

et al. 1997

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“…IL-4 and IL-10 were shown recently to be potent inducers of proliferation in B-CLL cells activated with the CD40 system [21]. In addition to their B cell stimulatory capacity antibodies to CD40 were also found to inhibit the growth of human B cell lymphoma cells [22].…”

Section: Introductionmentioning

confidence: 99%

CD40 Ligation Inhibits IL‐2 and SAC+IL‐2 Induced Proliferation in Chronic Lymphocytic Leukaemia Cells

et al. 1997

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Söderberg O, Christiansen I, Carlsson M, Nilsson K. CD40 Ligation Inhibits IL-2 and SACþIL-2 Induced Proliferation in Chronic Lymphocytic Leukaemia Cells. Scand J Immunol 1997;45:706-714 This paper reports on differences between B cell-type chronic lymphocytic leukaemia (B-CLL) and normal B cells in their response to IL-2þthioredoxin (Trx), Staphylococcus aureus Cowan strain 1 (SAC)þIL-2þTrx, and to CD40 ligation of IL-2þTrx and SACþIL-2þTrx stimulation. The authors found that Trx acted synergistically with IL-2 and SACþIL-2 in inducing DNA synthesis in B-CLL cells, but not in the normal B cells. Interestingly, IL-2þTrx alone was found to induce proliferation in B-CLL cells from patients with advanced stages of disease. In addition, we also found that IL-2þTrx and SACþIL-2þTrx-induced DNA synthesis of B-CLL cells was inhibited by CD40 activation (by soluble anti-CD40 MoAb and anti-CD40 MoAb presented on irradiated CD32L cells). In clear contrast, SACþIL-2þTrx-induced DNA synthesis of normal B cells was not inhibited by soluble anti-CD40 MoAb. The authors therefore conclude that B-CLL cells differ from normal B cells in their response to IL-2 (IL-2þTrx) and CD40 ligation.

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“…Triggering CD40 in B-cell lymphoma cell lines has been reported to suppress growth and induce apoptosis in some cases (Benoit & Wade, 1996;Bishop et al, 1998;Funakoshi et al, 1994). However, CD40 can also play an important role in promoting both normal and neoplastic B-cell proliferation and survival (An & Knox, 1996;Banchereau & Rousset, 1991;Choi et al, 1995;Ghia et al, 1998;Holden et al, 1993;Johnson et al, 1993;Kehry, 1996;Lùmo et al, 1997;Romano et al, 1998;Tsubata et al, 1993;Walker et al, 1997;Wang et al, 1996;Zhang et al, 1996a).…”

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confidence: 99%

Bryostatin and CD40‐ligand enhance apoptosis resistance and induce expression of cell survival genes in B‐cell chronic lymphocytic leukaemia

et al. 1999

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). CD40L and Bryostatin decreased both spontaneous and drug-induced apoptosis in most B-CLL specimens tested. Apoptosis resistance was associated with CD40L-and Bryostatin-induced elevations in the anti-apoptotic Bcl-2 family protein Mcl-1. CD40L also induced striking increases in the levels of the anti-apoptotic protein Bcl-X L in B-CLLs. CD40L stimulated increases in the surface expression of CD40, CD54, CD69, CD70, CD80 and CD95, whereas Bryostatin induced expression of CD40, CD54, CD69 and CD95 but not the co-stimulatory molecules CD70 and CD80. Despite elevations in the expression of CD95 (Fas), anti-Fas antibodies failed to induce apoptosis of CD40L-and Bryostatin-treated B-CLL cells. This Fasresistance was associated with increased expression of the Fas-antagonist Flip in CD40L-treated, and with elevations in the caspase inhibitor XIAP in Bryostatin-treated B-CLLs. The potential anti-apoptotic properties of CD40L and Bryostatin should be taken into consideration when employing these agents in clinical trials involving patients with B-CLL.

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Inhibition of human B-cell lymphoma growth by CD40 stimulation

Cited by 203 publications

References 22 publications

Role of the CD40 and CD95 (APO‐1/Fas) antigens in the apoptosis of human B‐cell malignancies

Role of the CD40 and CD95 (APO‐1/Fas) antigens in the apoptosis of human B‐cell malignancies

CD40 Ligation Inhibits IL‐2 and SAC+IL‐2 Induced Proliferation in Chronic Lymphocytic Leukaemia Cells

Bryostatin and CD40‐ligand enhance apoptosis resistance and induce expression of cell survival genes in B‐cell chronic lymphocytic leukaemia

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