Diminished production of interleukin‐6 in chronic lymphocytic leukaemia (B‐CLL) cells from patients at advanced stages of disease

Hulkkonen, Janne; Vilpo, Juhani; Vilpo, Leena; Hurme, Mikko

doi:10.1046/j.1365-2141.1998.00595.x

Cited by 24 publications

(19 citation statements)

References 31 publications

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“…Higher TNFα levels are associated with more aggressive disease [ 12 , 13 ], although CLL cells with aggressive clinical behavior make less TNFα than cells from patients with indolent disease. [ 13 , 18 , 22 ]. TNFα in the plasma of an additional 43 patients was found to correlate inversely with IgG level at the same time-point.…”

Section: Resultsmentioning

confidence: 99%

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia

et al. 2018

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The intrinsic humoral immunodeficiency of chronic lymphocytic leukemia (CLL) is often managed with immunoglobulin replacement therapy (IgRT) to maintain IgG levels in the low-normal range (6–8 g/L) but optimal targets for IgG and timing to commence IgRT are unclear. IgG levels fell near 6 g/L at rates of −0.85±0.14 g/L/year in 51 patients who required treatment for CLL within 4.5±0.4 years from initial diagnosis and − 0.27±0.04 g/L/year in 40 patients with progressive disease who remained untreated after 8.5±0.5 years. In contrast, endogenous IgG levels remained above 8 g/L in patients with highly indolent disease (n = 25) and TNFα and beta-2-microglobulin (β2M) in blood decreased when IgRT was used to increase IgG levels over 9 g/L. At 15 g/L but not 5 g/L, the IgRT product Hizentra® inhibited B cell receptor (BCR)-activation, TNFα production, and survival in vitro , particularly of CLL cells that spontaneously made little TNFα. These findings suggest deterioration of the humoral immune system is associated with progressive CLL and altering the dosing of IgRT to achieve higher than conventional IgG target levels may have therapeutic activity.

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Section: Resultsmentioning

confidence: 99%

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia

et al. 2018

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“…Several abnormalities of cytokine production have been described in CLL regarding both the B and T cell compartment, including reduced IL‐4, IFN‐γ (Hill et al , 1999) and IL‐6 (Hulkkonen et al , 1998), which have been related to the cellular and humoral immune defects of the disease. However, little is known about cytokine production by PNH lymphocytes, except for reduced IL‐2 release in patients with aplastic anaemia who progressed to clinical PNH (Nissen et al , 1999).…”

Section: Cytokine Production By Mitogen‐stimulated Blood Culturesmentioning

confidence: 99%

Biological and molecular characterization of PNH‐like lymphocytes emerging after Campath‐1H therapy

et al. 2001

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Campath‐1H, an anti‐CD52 monoclonal antibody, is therapeutically active in lymphoproliferative and autoimmune diseases. After Campath‐1H therapy, lymphocytes with a paroxysmal nocturnal haemoglobinuria (PNH) phenotype have been reported to emerge. We characterized a PNH‐like lymphocyte population emerging after Campath‐1H therapy, in a patient with fludarabine refractory B‐cell chronic lymphocytic leukaemia (B‐CLL). We demonstrated a reduction in PIG‐A mRNA levels compared with controls, and of all cytokines tested [interleukin (IL)‐4, IL‐13, IL‐2, interferon(IFN)‐γ, IL‐6, IL‐10, and tumour necrosis factor (TNF)‐α], except transforming growth factor (TGF)‐β. Given the inhibitory activity of TGF‐β, its elevated levels may contribute to the selective pressure of Campath‐1H, leading to the emergence of PNH‐like lymphocytes.

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“…Immunophenotyping was performed by¯ow cytometry (EPICS C, Coulter Electronics, Hialeach, CA; FACSCan and FACSCalibur, Becton Dickinson, San Jose, CA) using commercial mouse monoclonal antibodies and respective immunoglobulin isotype controls as recommended by the manufacturers (11).…”

Section: Flow Cytometrymentioning

confidence: 99%

Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro

Vilpo¹,

Koski²,

Vilpo³

2000

European J of Haematology

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The cytotoxicity of vincristine in vitro was investigated in B chronic lymphocytic leukemia (CLL) cells and in normal peripheral blood mononuclear cells. An approximately 25-fold selectivity towards leukemic vs. normal lymphocytes was demonstrated. Cells from patients having a mature subtype (CLL or CLL/mix) or a slowly progressing form of CLL were significantly more sensitive to vincristine in vitro than the cases with a CLL/PL phenotype or faster-progressing disease. Depending on the vincristine dose, the number of dead CLL cells accumulated slowly during the 4-d observation period. Our data indicate a marked individual variation in vincristine susceptibility among individual CLL cells. Vincristine induced annexin positivity, nuclear blebbing and DNA fragmentation in CLL cells. These indicate an "apoptosis-like" cell death. Since CLL cells are in the G0/G1 phase of the cell cycle, the only known mode of anticancer action of vinca alkaloids, i.e. anti-mitotic action, cannot explain the death of CLL cells. Furthermore, similar cellular uptake and efflux of vincristine by normal and CLL cells excluded pharmacokinetic differences as a cause of selectivity of vincristine towards leukemic lymphocytes. Immunostaining of filamentous structures of CLL cells revealed that vincristine brings about selective changes in alpha-tubulin but not in beta-actin or vimentin. Although the antitubulin action of vinca alkaloids in the biochemical sense is well demonstrated, this kind of anticancer effect has not previously been shown. Vincristine is used in several regimens for CLL, but its efficacy in CLL has never been demonstrated in a clinical context and its value in routine CLL chemotherapy has been questioned. The present data strongly support the need for further evaluation of the role and mode of action of vincristine in chemotherapy of CLL and other cancers as well.

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Diminished production of interleukin‐6 in chronic lymphocytic leukaemia (B‐CLL) cells from patients at advanced stages of disease

Cited by 24 publications

References 31 publications

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia

Association of blood IgG with tumor necrosis factor-alpha and clinical course of chronic lymphocytic leukemia

Biological and molecular characterization of PNH‐like lymphocytes emerging after Campath‐1H therapy

Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro

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