Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation:: induction of bax

被引:46
作者
Szocinski, JL
Khaled, AR
Hixon, J
Halverson, D
Funakoshi, S
Fanslow, WC
Boyd, A
Taub, DD
Durum, SK
Siegall, CB
Longo, DL
Murphy, WJ
机构
[1] NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[2] NCI, Lab Leukocyte Biol, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[3] NCI, Mol Immunoregulat Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[4] NIA, Immunol Lab, Baltimore, MD 21224 USA
[5] Immunex Corp, Seattle, WA USA
[6] Hood Coll, Dept Biol, Frederick, MD 21701 USA
[7] Seattle Genet, Bothell, WA USA
关键词
D O I
10.1182/blood.V100.1.217
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
CD40 is present on both normal and neoplastic B-lineage cells. CD40 stimulation of normal B cells has been shown to promote normal growth and differentiation, whereas aggressive histology B lymphomas are growth inhibited. The inhibition of neoplastic B-cell growth is believed to occur via activation-induced cell death in which stimuli that typically promote the growth of normal cells prevent the growth of their neoplastic counterparts. We show here that CD40 stimulation using either a soluble recombinant human CD40 ligand (srhCD40L) or anti-CD40 monoclonal antibody resulted in apoptosis of human Burkitt lymphoma cell lines. Additional studies examining the mechanism of CD40-mediated death revealed an increase in bax messenger RNA with a subsequent increase in Bax protein in the mitochondria of the treated cells. In vitro exposure of the cells to bax antisense oligonucleotides resulted in a significant decline in Bax protein levels and partial protection from CD40-mediated death, indicating that induction of Bax was at least one mechanism underlying this inhibitory effect of CD40 stimulation on lymphomas. When immunodeficient mice bearing Burkitt lymphoma were treated with srhCD40L, significant increases in survival were observed indicating a direct antitumor effect as a result of CD40 stimulation in vivo. Overall, these results demonstrate that CD40 ligation of aggressive histology B-lymphoma cells results in inhibition both in vitro and in vivo and thus may be of potential clinical use in their treatment.
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收藏
页码:217 / 223
页数:7
相关论文
共 38 条
  • [1] Inhibition of Bax channel-forming activity by Bcl-2
    Antonsson, B
    Conti, F
    Ciavatta, A
    Montessuit, S
    Lewis, S
    Martinou, I
    Bernasconi, L
    Bernard, A
    Mermod, JJ
    Mazzei, G
    Maundrell, K
    Gambale, F
    Sadoul, R
    Martinou, JC
    [J]. SCIENCE, 1997, 277 (5324) : 370 - 372
  • [2] MOLECULAR AND BIOLOGICAL CHARACTERIZATION OF A MURINE LIGAND FOR CD40
    ARMITAGE, RJ
    FANSLOW, WC
    STROCKBINE, L
    SATO, TA
    CLIFFORD, KN
    MACDUFF, BM
    ANDERSON, DM
    GIMPEL, SD
    DAVISSMITH, T
    MALISZEWSKI, CR
    CLARK, EA
    SMITH, CA
    GRABSTEIN, KH
    COSMAN, D
    SPRIGGS, MK
    [J]. NATURE, 1992, 357 (6373) : 80 - 82
  • [3] CD40 LIGAND IS A T-CELL GROWTH-FACTOR
    ARMITAGE, RJ
    TOUGH, TW
    MACDUFF, BM
    FANSLOW, WC
    SPRIGGS, MK
    RAMSDELL, F
    ALDERSON, MR
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1993, 23 (09) : 2326 - 2331
  • [4] T-CELL TUMOR ELIMINATION AS A RESULT OF T-CELL RECEPTOR MEDIATED ACTIVATION
    ASHWELL, JD
    LONGO, DL
    BRIDGES, SH
    [J]. SCIENCE, 1987, 237 (4810) : 61 - 64
  • [5] Prolonged phenotypic, functional, and molecular change in group I Burkitt lymphoma cells on short-term exposure to CD40 ligand
    Baker, MP
    Eliopoulos, AG
    Young, LS
    Armitage, RJ
    Gregory, CD
    Gordon, J
    [J]. BLOOD, 1998, 92 (08) : 2830 - 2843
  • [6] ANTI-IGM INDUCES TRANSFORMING GROWTH-FACTOR-BETA SENSITIVITY IN A HUMAN B-LYMPHOMA CELL-LINE - INHIBITION OF GROWTH IS ASSOCIATED WITH A DOWN-REGULATION OF MUTANT P53
    BECKWITH, M
    RUSCETTI, FW
    SING, GK
    URBA, WJ
    LONGO, DL
    [J]. BLOOD, 1995, 85 (09) : 2461 - 2470
  • [7] Molecules in focus -: Bax.: The pro-apoptotic Bcl-2 family member, Bax
    Brady, HJM
    Gil-Gómez, G
    [J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1998, 30 (06) : 647 - 650
  • [8] BCL-2 FAMILY: Regulators of cell death
    Chao, DT
    Korsmeyer, SJ
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 1998, 16 : 395 - 419
  • [9] ACTIVATION OF HUMAN B-CELLS MEDIATED THROUGH 2 DISTINCT CELL-SURFACE DIFFERENTIATION ANTIGENS, BP35 AND BP50
    CLARK, EA
    LEDBETTER, JA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (12) : 4494 - 4498
  • [10] FLUCKIGER AC, 1992, BLOOD, V80, P3173