Impaired Cytotoxic Activity of Interleukin 2 (IL 2)-cultured Large Granular Lymphocytes (LGL) in Childhood Acute Lymphoblastic Leukemia. Quantitative Measurement of IL 2 Receptor Expression of IL 2-cultured LGL

Abstract A 14-year-old Japanese female with neutropenia showed malignant proliferation of the large granular lymphocytes (LGLs). These LGLs were E rosette+ and Fc(IgG) receptor+ and therefore are referred to as T gamma lymphocytes. They were also Leu-11+ and OKT11+; however, they were clearly negative for Leu-7, OKT3, OKT8, OKM1, and HNK-1 antigens as well as for terminal deoxynucleotidyl transferase activity. Karyotype analysis revealed 47, XXX. The LGLs showed no rearrangement of T cell receptor C beta genes. The natural killer (NK) cell activity against K562 target cells was low, but was significantly augmented after stimulation by recombinant human interleukin 2 (IL 2) in contrast to minimal NK boosting by recombinant human gamma-interferon (gamma- IFN). Such a unique responsive ability to lymphokines was quite similar to that noted in fetal and cord blood cells. These LGLs also demonstrated a considerable increase in antibody-dependent cell- mediated cytotoxicity (ADCC) and lymphokine-activated killer (LAK) activity after a short incubation with IL 2. Although in a resting stage they showed no IL 2 receptor expression as examined by anti-Tac antibody, Tac antigen appeared after IL 2 treatment followed by a marked increase in 3H-thymidine incorporation and a remarkable production of gamma-IFN. To investigate the mechanism of neutropenia, in vitro IL 2-stimulated coculture studies of these cells with normal bone marrow cells were performed. Colony formation of myeloid progenitors (CFU-C) was significantly suppressed. In addition, the conditioned medium from IL 2-stimulated LGLs indicated a remarkable suppression of CFU-C. These results suggest that these LGLs with a Leu- 11+, Leu-7- surface phenotype might belong to a unique subset of pre-NK cells that are functionally and phenotypically similar to those represented at any early stage of human ontogeny and that they strongly express Tac antigen under the influence of IL 2 administration, followed by remarkable cell proliferation and gamma-IFN production.

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Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor α-chain predicts a poor prognosis

Leukemia ◽

10.1038/sj.leu.2404497 ◽

2007 ◽

Vol 21 (2) ◽

pp. 326-332 ◽

Cited By ~ 29

Author(s):

K Nakase ◽

K Kita ◽

H Miwa ◽

K Nishii ◽

M Shikami ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Interleukin 2 ◽

Receptor Expression ◽

Cytokine Receptor ◽

Interleukin 2 Receptor ◽

Adult Acute Lymphoblastic Leukemia ◽

Α Chain

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Malignant clonal expansion of large granular lymphocytes with a Leu- 11+, Leu-7- surface phenotype: in vitro responsiveness of malignant cells to recombinant human interleukin 2

Blood ◽

10.1182/blood.v68.5.1065.bloodjournal6851065 ◽

1986 ◽

Vol 68 (5) ◽

pp. 1065-1073 ◽

Cited By ~ 1

Author(s):

S Koizumi ◽

H Seki ◽

T Tachinami ◽

M Taniguchi ◽

A Matsuda ◽

...

Keyword(s):

Interleukin 2 ◽

Receptor Expression ◽

Terminal Deoxynucleotidyl Transferase ◽

Target Cells ◽

Transferase Activity ◽

Large Granular Lymphocytes ◽

Surface Phenotype ◽

Granular Lymphocytes ◽

Leu 7

A 14-year-old Japanese female with neutropenia showed malignant proliferation of the large granular lymphocytes (LGLs). These LGLs were E rosette+ and Fc(IgG) receptor+ and therefore are referred to as T gamma lymphocytes. They were also Leu-11+ and OKT11+; however, they were clearly negative for Leu-7, OKT3, OKT8, OKM1, and HNK-1 antigens as well as for terminal deoxynucleotidyl transferase activity. Karyotype analysis revealed 47, XXX. The LGLs showed no rearrangement of T cell receptor C beta genes. The natural killer (NK) cell activity against K562 target cells was low, but was significantly augmented after stimulation by recombinant human interleukin 2 (IL 2) in contrast to minimal NK boosting by recombinant human gamma-interferon (gamma- IFN). Such a unique responsive ability to lymphokines was quite similar to that noted in fetal and cord blood cells. These LGLs also demonstrated a considerable increase in antibody-dependent cell- mediated cytotoxicity (ADCC) and lymphokine-activated killer (LAK) activity after a short incubation with IL 2. Although in a resting stage they showed no IL 2 receptor expression as examined by anti-Tac antibody, Tac antigen appeared after IL 2 treatment followed by a marked increase in 3H-thymidine incorporation and a remarkable production of gamma-IFN. To investigate the mechanism of neutropenia, in vitro IL 2-stimulated coculture studies of these cells with normal bone marrow cells were performed. Colony formation of myeloid progenitors (CFU-C) was significantly suppressed. In addition, the conditioned medium from IL 2-stimulated LGLs indicated a remarkable suppression of CFU-C. These results suggest that these LGLs with a Leu- 11+, Leu-7- surface phenotype might belong to a unique subset of pre-NK cells that are functionally and phenotypically similar to those represented at any early stage of human ontogeny and that they strongly express Tac antigen under the influence of IL 2 administration, followed by remarkable cell proliferation and gamma-IFN production.

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Prolonged defects of interleukin-2 production, responsiveness, and receptor expression in patients with acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v73.6.1608.bloodjournal7361608 ◽

1989 ◽

Vol 73 (6) ◽

pp. 1608-1614

Author(s):

MS Borzy ◽

D Ridgway

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Cell Surface ◽

Lymphoblastic Leukemia ◽

Interleukin 2 ◽

Receptor Expression ◽

Cell Surface Receptors ◽

Con A ◽

Surface Receptors ◽

Control Subjects ◽

Patient Groups

The proliferative responsiveness to, production of, and the expression of cell-surface receptors for interleukin-2 (IL-2) were examined in 14 children with acute lymphoblastic leukemia (ALL) in remission and receiving maintenance chemotherapy for 6 to 35 months; in 19 children with ALL in remission and off all therapy for 2 to 138 months; and 15 control subjects. Short-term concanavalin A (Con A)-activated, purified T lymphocytes from patients on, as well as patients off, therapy had a significantly decreased proliferative responsiveness to a saturating amount of exogenous, recombinant IL-2 as compared to control subjects (P less than 0.005 and less than 0.05, respectively). Phytohemagglutinin (PHA)-stimulated IL-2 production by peripheral blood mononuclear cells (PBMC) was also substantially decreased in both patient groups with the median values of IL-2 produced being 2.2, 2.1, and 8.1 U/mL in the on therapy, off therapy, and control groups, respectively. In addition, PHA-induced expression of cell-surface receptors for IL-2 on PBMC was significantly decreased in both patient groups as compared to control subjects (P less than 0.01). Lymphocyte proliferation to mitogens (PHA, Con A, and pokeweed mitogen) was similar in all three groups studied. These results demonstrate that substantial quantitative and qualitative abnormalities of the IL-2-T lymphocyte system are present in the majority of treated patients with ALL, not only during maintenance therapy, but also for a prolonged period after the cessation of all chemotherapy. These long-lasting defects of the IL-2 system are most likely a late effect of chemotherapy and may result in increased complications in some long- term survivors of ALL.

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