Quantification and phenotypic characterization of peripheral blood Vδ1 + T cells in chronic lymphocytic leukemia and monoclonal B cell lymphocytosis

Abstract The mechanism of the hypogammaglobulinemia in patients with chronic lymphocytic leukemia (CLL) was studied by determining the generation of specific immunoglobulin-secreting cells in response to mitogen and antigen stimulation in culture. Normal peripheral blood B lymphocytes from 18 normal subjects cocultured with equal numbers of autologous T cells generated cells secreting 2,542 +/- 695 IgG, 2,153 +/- 615 IgA, and 2,918 +/- 945 IgM. Normal B lymphocytes cocultured with normal allogeneic T cells generated similar numbers. However, B lymphocytes from patients with chronic lymphocytic leukemia cocultured with T cells from the same patient generated only 0.5% as many cells secreting IgG and 11% and 23% as many secreting IgA and IgM, respectively. The reason for this markedly defective generation of immunoglobulin-secreting cells was investigated by evaluating T-helper, T-suppressor, and B-cell function using B cells from tonsil and T and B cells from peripheral blood of normal and leukemic individuals. T cells from patients with chronic lymphocytic leukemia provided somewhat greater help than did normal T cells to normal peripheral blood B cells and normal help to tonsil B cells, whether stimulated with mitogen or antigen. T cells from patients with chronic lymphocytic leukemia did not demonstrate increased suppressor function compared to normals with B cells from normal peripheral blood. The hypogammaglobulinemia in these patients therefore was associated with a markedly defective generation of immunoglobulin secreting cells, and as there was normal or increased T- cell helper activity without excessive suppressor activity, it seems likely that this was due to an intrinsic B-cell defect.

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Human Vδ1 γδ T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells

Cytotherapy ◽

10.3109/14653249.2011.553595 ◽

2011 ◽

Vol 13 (6) ◽

pp. 753-764 ◽

Cited By ~ 48

Author(s):

Gabrielle M. Siegers ◽

Helena Dhamko ◽

Xing-Hua Wang ◽

A. Mark Mathieson ◽

Yoko Kosaka ◽

...

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Peripheral Blood ◽

Γδ T Cells ◽

Lymphocytic Leukemia ◽

Specific Cytotoxicity ◽

Cell Chronic Lymphocytic Leukemia

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Immunoglobulin secretory function of B cells from untreated patients with chronic lymphocytic leukemia and hypogammaglobulinemia: role of T cells

Blood ◽

10.1182/blood.v62.4.767.bloodjournal624767 ◽

1983 ◽

Vol 62 (4) ◽

pp. 767-774 ◽

Cited By ~ 1

Author(s):

LA Fernandez ◽

JM MacSween ◽

GR Langley

Keyword(s):

T Cells ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

B Lymphocytes ◽

Peripheral Blood ◽

Cell Function ◽

Lymphocytic Leukemia ◽

Suppressor Activity ◽

Normal Peripheral Blood

The mechanism of the hypogammaglobulinemia in patients with chronic lymphocytic leukemia (CLL) was studied by determining the generation of specific immunoglobulin-secreting cells in response to mitogen and antigen stimulation in culture. Normal peripheral blood B lymphocytes from 18 normal subjects cocultured with equal numbers of autologous T cells generated cells secreting 2,542 +/- 695 IgG, 2,153 +/- 615 IgA, and 2,918 +/- 945 IgM. Normal B lymphocytes cocultured with normal allogeneic T cells generated similar numbers. However, B lymphocytes from patients with chronic lymphocytic leukemia cocultured with T cells from the same patient generated only 0.5% as many cells secreting IgG and 11% and 23% as many secreting IgA and IgM, respectively. The reason for this markedly defective generation of immunoglobulin-secreting cells was investigated by evaluating T-helper, T-suppressor, and B-cell function using B cells from tonsil and T and B cells from peripheral blood of normal and leukemic individuals. T cells from patients with chronic lymphocytic leukemia provided somewhat greater help than did normal T cells to normal peripheral blood B cells and normal help to tonsil B cells, whether stimulated with mitogen or antigen. T cells from patients with chronic lymphocytic leukemia did not demonstrate increased suppressor function compared to normals with B cells from normal peripheral blood. The hypogammaglobulinemia in these patients therefore was associated with a markedly defective generation of immunoglobulin secreting cells, and as there was normal or increased T- cell helper activity without excessive suppressor activity, it seems likely that this was due to an intrinsic B-cell defect.

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Emergence of a B-cell lymphoblastic lymphoma in a patient with B-cell chronic lymphocytic leukemia: evidence for the single-cell origin of the two tumors

Blood ◽

10.1182/blood.v78.3.797.bloodjournal783797 ◽

1991 ◽

Vol 78 (3) ◽

pp. 797-804

Author(s):

V Pistoia ◽

S Roncella ◽

PF Di Celle ◽

M Sessarego ◽

G Cutrona ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Lines ◽

Peripheral Blood ◽

Chromosomal Abnormalities ◽

Cell Clone ◽

Lymphoblastic Lymphoma ◽

Lymphocytic Leukemia ◽

Terminal Deoxynucleotidyl Transferase ◽

Chain Gene

A patient is described who presented with a chronic lymphocytic leukemia (CLL) and later developed a lymphoblastic lymphoma. The cells from the CLL were typical mature B lymphocytes as could be assessed by morphologic, cytochemical, and surface marker analyses. The cells from the lymphoblastic lymphoma were immature B cells that expressed CD10, CD20, and HLA-DR markers, but not surface Ig or cytoplasmic mu chains, and were negative for terminal deoxynucleotidyl transferase (TdT). The cells of two continuous cell lines, obtained from the bone marrow and the peripheral blood of the patient, had the same phenotype as the lymphoblastic lymphoma cells, did not contain the Epstein-Barr virus genome, and displayed malignant features in vitro, including the capacity to form colonies in agar. The two cell lines also shared identical chromosomal abnormalities, a finding which suggests that they derived from the same malignant cell already present in vivo. Such chromosomal abnormalities were not seen in the karyotype of the peripheral blood cells at the onset of the disease. Analysis of the Ig heavy chain genes using a DJ-specific probe showed the very same monoclonal rearrangement in the cells from the B-CLL, the lymphoblastic lymphoma and the two cell lines, thus demonstrating their common clonal origin. By contrast, a monoclonal rearrangement of the lambda chain gene locus was found in the B-CLL cells only, a finding consistent with their exclusive capacity to express surface IgM lambda. This patient represents a rare case in whom a chronic lymphoproliferative disorder with mature malignant cells transforms into a lymphoblastic lymphoma characterized by cells frozen at a very early maturational stage. The possible mechanisms leading to such transformation within the same cell clone are discussed.

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Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v71.4.1012.bloodjournal7141012 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1012-1020 ◽

Cited By ~ 1

Author(s):

JS Moore ◽

MB Prystowsky ◽

RG Hoover ◽

EC Besa ◽

PC Nowell

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Specific Immunoglobulin ◽

Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

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Antigen presentation in an HLA-DR-restricted fashion by B-cell chronic lymphocytic leukemia cells

Blood ◽

10.1182/blood.v72.1.102.bloodjournal721102 ◽

1988 ◽

Vol 72 (1) ◽

pp. 102-108 ◽

Cited By ~ 7

Author(s):

M Yasukawa ◽

T Shiroguchi ◽

A Inatsuki ◽

Y Kobayashi

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Antigen Presentation ◽

Interleukin 2 ◽

Class Ii ◽

Hla Class Ii ◽

Lymphocytic Leukemia ◽

Hla Dr ◽

Cell Chronic Lymphocytic Leukemia

The ability of B-cell chronic lymphocytic leukemia (B-CLL) cells to present antigen to antigen-specific T cells was investigated. B-CLL cells present herpes simplex virus (HSV) antigen and purified protein derivative (PPD) to HSV- and PPD-specific, interleukin-2-dependent T- cell lines in an antigen-specific manner. Treatment of B-CLL cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induced markedly increased levels of HLA-DR expression. TPA-treated B-CLL cells showed substantially more effective presentation, especially at low antigen concentrations, than did untreated B-CLL cells. By coculturing different allogeneic combinations of B-CLL cells and T cells and by adding anti-HLA-DR monoclonal antibody to cultures, it was found that antigen presentation by B-CLL cells was restricted by HLA-DR in the same way as for macrophages. We concluded from these experiments that B- CLL cells have a capacity to serve as antigen-presenting cells in an HLA class II-restricted fashion and that increasing the amount of HLA class II antigen and activation of B-CLL cells resulted in effective antigen presentation.

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Expansion of effector T cells associated with decreased PD-1 expression in patients with indolent B cell lymphomas and chronic lymphocytic leukemia

Leukemia & Lymphoma ◽

10.3109/10428194.2012.673224 ◽

2012 ◽

Vol 53 (9) ◽

pp. 1785-1794 ◽

Cited By ~ 20

Author(s):

Sanne H. Tonino ◽

Pablo J. van de Berg ◽

Si La Yong ◽

Ineke J. Ten Berge ◽

Marie José Kersten ◽

...

Keyword(s):

T Cells ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Effector T Cells ◽

Lymphocytic Leukemia ◽

B Cell Lymphomas

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Characterization of the phytohemagglutinin-induced proliferating lymphocyte subpopulations in chronic lymphocytic leukemia patients using a clonogenic agar technique and monoclonal antibodies

Blood ◽

10.1182/blood.v58.5.1053.1053 ◽

1981 ◽

Vol 58 (5) ◽

pp. 1053-1055 ◽

Cited By ~ 20

Author(s):

S Davis

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

Chronic Lymphocytic Leukemia ◽

B Lymphocytes ◽

Peripheral Blood Lymphocytes ◽

Lymphocytic Leukemia ◽

Helper T Cells ◽

Suppressor T Lymphocytes ◽

Pha Stimulation

Abstract Peripheral blood lymphocytes from normal donors and patients with chronic lymphocytic leukemia, B-cell type, were purified into T, helper T, and suppressor T lymphocytes by fluorescence-activated cell sorting using OKT3, OKT4, and OKT8 monoclonal antibodies. The maximum response of the purified subpopulations to stimulation by phytohemagglutinin (PHA) was determined by measuring the production of colonies when the stimulated cells were grown on agar. The helper T cells in normal and CLL patients were the most responsive to PHA stimulation, although the responsiveness of helper T cells to PHA was decreased in CLL. Purified CLL B cells responded minimally to PHA stimulation, but normal B lymphocytes did not. The abnormal response of CLL lymphocytes to PHA appears to be due abnormal helper T cells, and, to a smaller extent, to the ability of CLL B lymphocytes to respond.

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Association between clonogenic cell growth and clinical risk group in B- cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v76.1.142.142 ◽

1990 ◽

Vol 76 (1) ◽

pp. 142-149 ◽

Cited By ~ 6

Author(s):

R Dadmarz ◽

SN Rabinowe ◽

SA Cannistra ◽

JW Andersen ◽

AS Freedman ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Cell Growth ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Risk Groups ◽

Lymphocytic Leukemia ◽

Cloning Efficiency ◽

Activated T Cells ◽

Clonogenic Cells

Abstract Chronic lymphocytic leukemia of B-cell origin (B-CLL) is a disease with a variable clinical course, despite the fact that the neoplastic cells in this disorder are homogeneous with respect to morphology, immunophenotype, and cell cycle stage. To further investigate the heterogeneity observed in the clinical behavior of B-CLL, we determined the phenotype and growth requirements of clonogenic cells from 28 patients with B-CLL from low-, intermediate-, and high-risk groups as defined by the Rai staging system. Using methyl-cellulose as a semi- solid media with feeder cells and/or growth factors, colonies were observed with one or more of the culture conditions tested in 25 of 28 CLLs. Phenotypic analysis of colonies demonstrated that the clonogenic cells uniformly expressed la, CD19, CD20, CD5, and the identical light chain as the original CLL cell cultured. However, heterogeneity was observed in clonogenic B-CLL cell growth among the three different CLL risk groups. Clonogenic cells from patients with low-risk CLL required either irradiated unstimulated T cells, with or without conditioned media (CM) or irradiated activated T cells alone for colony formation. Both the number of colonies (227 +/- 15) as well as the number of cells per colony (220 +/- 82) were large, with a mean cloning efficiency of 0.39%. In contrast, clonogenic cells from patients with intermediate- and high-risk CLL required the combination of both irradiated activated T cells and CM. As compared with the low-risk CLLs, both the number and size of the colonies formed by the intermediate- (74 +/- 17, 70 +/- 39) and high- (83 +/- 28, 40 +/- 14) risk groups were significantly lower (P less than .0001). Similarly, the mean cloning efficiency was significantly reduced to 0.15% and 0.14%, respectively. None of the recombinant cytokines (interleukin 1 [IL-1] to IL-7, tumor necrosis factor, alpha and gamma-interferon, B-cell growth factor, and granulocyte macrophage colony-stimulating factor) alone or in combination with each other could entirely replace the stimulatory effect of the activated T cells. These data suggest that clinical progression of B-CLL is associated with a loss of clonogenic potential in the circulating pool of neoplastic cells, which require as yet undefined factors provided by activated T cells and CM.

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