Soluble CD40 ligand induces selective proliferation of lymphoma cells in primary mantle cell lymphoma cell cultures.

Interaction between CD40 and the CD40 ligand (CD40L) is critical for the survival and proliferation of B cells during immunopoiesis. However, the role of CD40L in the pathogenesis of malignant lymphomas is ambiguous. Primary mantle cell lymphoma (MCL) cells were cultured in the presence of recombinant human CD40L trimer (huCD40LT), and a significant time- and dose-dependent induction of DNA synthesis was observed in thymidine incorporation assays (n = 7, P <.04). The maximal rate of DNA synthesis was reached at huCD40LT doses of 100 ng/mL and above after 4 days of culture, but a significant increase of DNA synthesis was detected already at doses of 1 ng/mL (P =.03). HuCD40LT never inhibited the basal level of DNA synthesis. These findings established 400 ng/mL of huCD40LT for 4 days as standard conditions in the system. Under these conditions, huCD40LT significantly increased the proportion of cells in the S/G(2)/M phases of the cell cycle in 4 of 7 studied cases, while the fraction of apoptotic cells remained unchanged (n = 7). HuCD40LT also induced expression of CD80/B7-1, CD86/B7-2, and CD95/Fas and up-regulated the expression of HLA-DR (n = 6). With the use of bromodeoxyuridine incorporation in triple-color flow cytometric analysis, it was found that huCD40LT induced cell-cycle progression in light chain-restricted cells only, of which a median of 14% (range, 0.5% to 29%; n = 4) returned to G(0/1) phase DNA content after bromodeoxyuridine incorporation, demonstrating completion of at least one cell cycle in the presence of huCD40LT. Thus, primary clonal MCL cells are activated and can proliferate in the presence of huCD40LT as a single agent.

[1]  N. Takakura,et al.  PRAD1 gene over‐expression in mantle‐cell lymphoma but not in other low‐grade B‐cell lymphomas, including extranodal lymphoma , 1994, British journal of haematology.

[2]  I Nicoletti,et al.  A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. , 1991, Journal of immunological methods.

[3]  W Hiddemann,et al.  Lymphoma classification--the gap between biology and clinical management is closing. , 1996, Blood.

[4]  M. Lipinski,et al.  Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype. , 1987, Journal of immunology.

[5]  J. Bartek,et al.  The retinoblastoma protein pathway in cell cycle control and cancer. , 1997, Experimental cell research.

[6]  C. Maliszewski,et al.  Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion , 1992, The Journal of experimental medicine.

[7]  F. Chiodi,et al.  Nerve growth factor released by CD40 ligand-transfected l cells: implications for functional and phenotypic studies on CD40+ cells. , 1998, Blood.

[8]  D. Longo,et al.  Inhibition of human B-cell lymphoma growth by CD40 stimulation. , 1994, Blood.

[9]  R. Noelle,et al.  The role of CD40 in the regulation of humoral and cell-mediated immunity. , 1994, Immunology today.

[10]  W. Telford,et al.  Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4 , 2000, Leukemia.

[11]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[12]  J. Gribben,et al.  High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  R. Armitage,et al.  Repression of apoptosis in human B-lymphoma cells by CD40-ligand and Bcl-2: relationship to the cell-cycle and role of the retinoblastoma protein. , 1996, Oncogene.

[14]  T. Kipps,et al.  Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal , 1993, The Journal of experimental medicine.

[15]  J. Gordon.  CD40 and its ligand: central players in B lymphocyte survival, growth, and differentiation. , 1995, Blood reviews.

[16]  P. Hokland,et al.  Optimization of a flow cytometric method for the simultaneous measurement of cell surface antigen, DNA content, and in vitro BrdUrd incorporation into normal and malignant hematopoietic cells. , 1998, Cytometry.

[17]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[18]  L. Notarangelo,et al.  Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM , 1993, Nature.

[19]  R. Willemze,et al.  Proliferation of B cell malignancies in all stages of differentiation upon stimulation in the 'CD40 system'. , 1996, Leukemia.

[20]  W. Hiddemann,et al.  Stimulation of B-chronic lymphocytic leukemia cells by murine fibroblasts, IL-4, anti-CD40 antibodies, and the soluble CD40 ligand. , 1997, Experimental hematology.

[21]  J.M. Adams,et al.  Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. , 1994, The EMBO journal.

[22]  R. Flavell,et al.  Expansion or Elimination of B Cells In Vivo: Dual Roles for CD40- and Fas (CD95)-Ligands Modulated by the B Cell Antigen Receptor , 1996, Cell.

[23]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[24]  J. Gordon,et al.  Prolonged phenotypic, functional, and molecular change in group I Burkitt lymphoma cells on short-term exposure to CD40 ligand. , 1998, Blood.

[25]  J. Belmont,et al.  CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome , 1993, Science.

[26]  A. Challa,et al.  Minimal cross-linking and epitope requirements for CD40-dependent suppression of apoptosis contrast with those for promotion of the cell cycle and homotypic adhesions in human B cells. , 1999, International immunology.

[27]  G. Ott,et al.  Genetic lesions in mantle cell lymphoma. , 1997, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[28]  S. Asano,et al.  Detection of cyclin D1 (bcl-1, PRAD1) overexpression by a simple competitive reverse transcription-polymerase chain reaction assay in t(11;14)(q13;q32)-bearing B-cell malignancies and/or mantle cell lymphoma. , 1997, Blood.

[29]  J. Gribben,et al.  Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Gribben,et al.  Failure of immunologic purging in mantle cell lymphoma assessed by polymerase chain reaction detection of minimal residual disease. , 1997, Blood.

[31]  I. Maclennan,et al.  Mechanism of antigen-driven selection in germinal centres , 1989, Nature.

[32]  I. Stamenkovic,et al.  The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co‐stimulatory activity. , 1992, The EMBO journal.

[33]  M. Salmon,et al.  Differential responses to CD40 ligation among Burkitt lymphoma lines that are uniformly responsive to Epstein-Barr virus latent membrane protein 1. , 1999, Journal of immunology.

[34]  N. Harris,et al.  PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. , 1991, Proceedings of the National Academy of Sciences of the United States of America.