Increased cytotoxicity against B-chronic lymphocytic leukemia by cellular manipulations: Potentials for therapeutic use

U. E. Vu, Z. S. Pavletic, X. Wang, S. S. Joshi

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

B-cell chronic lymphocytic leukemia (CLL) is characterized by profound immune dysfunction and a marked resistance to apoptosis. Understanding the cellular biology of immune effector cells from CLL patients as well as leukemic target cells in essential to developing immune mediated therapeutic strategies for CLL. In this study, an immortal CLL cell line called WSU-CLL has been used to study the characteristics of B-cell CLL as a tumor target for natural killer (NK), activated natural killer, and lymphokine activated killer (LAK) cells. The WSU-CLL cells were significantly less (p<0.0001) susceptible to NK cell mediated cytotoxicity compared to K562, a standard tumor target cell line. In vitro activation of effector cells with either short term, low dose IL-2 or long term, high dose IL-2 significantly increased the susceptibility of CLL cells for cell mediated killing. The addition of CD1a+/CD3-/CD4+/CD80+/CD83+ dendritic cells derived from human umbilical cord blood increased the cytotoxicity of LAK cells againts WSU-CLL. There is an increased expression of Bcl-2 and decreased expression of Fas on WSU-CLL cells as determined by RT-PCR techniques indicating possible roles for these genes in exerting resistance to immune cell mediated lysis. When Bcl-2 expression was downregulated in WSU-CLL cells using gene specific antisense oligonucleotides, the susceptibility of WSU-CLL cells to the cytotoxicity of chemotherapeutic agent Fludarabine was increased. Thus, our results suggests that in vitro activation with cytokines, addition of accesosry cell populations such as dendritic cells and/or manipulation of key gene expression i.e. down regulation of Bcl-2 might be potential strategies to increase the antitumor cytotoxicity againts CLL cells.

Original languageEnglish (US)
Pages (from-to)573-582
Number of pages10
JournalLeukemia and Lymphoma
Volume39
Issue number5-6
DOIs
StatePublished - 2000

Keywords

  • Antisense therapy
  • B-chronic lymphocytic leukemia
  • Bcl-2
  • Cytotoxicity
  • Dendritic cells
  • Fludarabine

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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