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PubMed1989

Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis.

B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B-cell Ig production/secretion by CD16+, CD3- blood cells.

Agammaglobulinemia↗

PubMed1987

Functional heterogeneity of B-CLL lymphocytes: dissociated responsiveness to growth factors and distinct requirements for a first activation signal.

We studied the effects of B cell directed growth factors on B lymphocytes from 11 patients with chronic lymphocytic leukemia (B-CLL). B-CLL lymphocytes were costimulated with anti-mu antibody (Ab) and with three growth factor preparations: recombinant IL2, B cell growth factor (BCGF) (20 kiloDalton (kD) BCGF) and a high molecular weight BCGF (50 kD BCGF). IL2 was the more active factor (in six of 11 patients). The effect of IL2 was dependent on a costimulation with anti-mu Ab or occurred independently of anti-mu Ab, according to the patients. This pattern of reactivity did not correlate with the presence or absence of the IL2 receptor (IL2-R) molecule on fresh B-CLL lymphocytes. Five patients responded to the 20 kD BCGF. Although four of them were also strong responders to IL2, one strongly responded to the 20 kD BCGF and did not respond to IL2. Only one patient responded to the 50 kD BCGF. When an anti-IL2-R Ab was introduced into the culture, only the responsiveness to IL2 was abolished: thus both 20 kD and 50 kD BCGFs activate B-CLL lymphocytes independently of the IL2-R. These results show that several B cell directed growth factors can act independently to support the proliferation of B-CLL lymphocytes.

Antigens, Surface↗

PubMed1988

Evidence for tumor reduction in refractory or relapsed B-CLL patients with infusional interleukin-2.

Recombinant interleukin-2 (rIL-2) is a biologic response modifier that is capable of enhancing or restoring the cytolytic capacity of large granular lymphocytes (LGL). We utilized this biologic response modifier in the treatment of B-chronic lymphocytic leukemia (B-CLL), a disease frequently characterized by deficient or absent natural killer activity. B-CLL (n = 12) patients previously refractory to chemotherapy or with progressive disease post cessation of chemotherapy were eligible. rIL-2 was given as i.v. infusion (2 x 10(6) units/m2) over 2 h 5 times per week for 3 weeks as induction. Responding patients were placed on maintenance therapy. Although there were no complete or partial responses (by ECOG criteria) there was clear evidence of tumor reduction. Seven of 10 evaluable patients had a reduction of the peripheral blood B cell clone, 3 had node reduction and 2 had reduction in their splenomegaly. All patients experienced mild to moderate toxicity and 1 patient died while on induction therapy. Three B-CLL patients following induction rIL-2 treatment were placed back on chemotherapy because of progressive disease. Interestingly, these 2 B-CLL patients achieved extremely rapid and complete responses to chemotherapy which had previously been ineffective. These data suggest a possible role for rIL-2 in treatment of B-CLL.

Aged↗

PubMed1982

Studies of human T gamma cells: division of a T gamma subset in normal and leukemic cells by using anti-T gamma-CLL heteroantiserum.

A specific heteroantiserum was prepared against the leukemic cells from a patient with T-derived chronic lymphocytic leukemia (T-CLL). The anti-serum was absorbed with cells of a morphologically different type from another patient with T-CLL. Both the immunizing cells and absorbing cells had Fc receptor for IgG (Fc gamma R), so the former case was named T gamma-CLL type 1, and the latter T gamma-CLL type 2. This antiserum, termed anti-T gamma-1, reacted with 19% of normal peripheral blood T lymphocytes, but not with non-T lymphocytes or monocytes. The T lymphocytes in the blood that reacted to anti-T gamma-1 were 72% of the T gamma cells. Anti-T gamma-1 also reacted to 60-78% of the thymocytes. Except for T gamma-CLL type 1 cells, anti-T gamma-1 did not react with various types of leukemia cells from lymphoid malignancies, myelogenous leukemias and monocytic leukemias. Studies on the relation between anti-T gamma-1 and OKT8 monoclonal antibody revealed that anti-T gamma-1 reactive (anti-T gamma-1+) cells and OKT8+ cells largely overlapped, but they were different in part. More interestingly, OKT8 inhibited Fc gamma R binding, but anti-T gamma-1 did not. These results indicate that anti-T gamma-1 is useful for detecting a certain subset of T cells and for classifying lymphoproliferative disorders.

Antibodies, Monoclonal↗

PubMedDate not supplied

A subpopulation of lymph node B-CLL cells expresses the common acute lymphoblastic leukemia antigen.

Tumoral lymph nodes (LN) from 7 B-CLL patients were studied with a panel of monoclonal antibodies and in situ immunohistochemical technique. The large majority of LN B-CLL cells carried the phenotype slg+ BA-1+OKIal+ and was admixed with variable numbers of helper/inducer and suppressor/cytotoxic T-cells. In each of the LN studied, regularly distributed, scattered J5+TdT-BA-3- small lumphoid cells were observed, showing no topographical predilection, nor tendency to cluster. J5+ small lymphoid cells may represent pre-B cells which have entered the LN and proliferate and mature in situ, giving rise to a leukemic sIg+OKIal+BA-1+J5- population. This would explain the early generalized LN involvement in B-CLL, and is in agreement with cell-kinetic and compartment in B-CLL LN. Alternatively, J5+ small lymphoid cells may represent a subset of LN B-CLL cells which have acquired the common acute lymphoblastic leukemia antigen during some transformation.

Antibodies, Monoclonal↗

PubMed1984

Soluble factor(s) released by Concanavalin A activated lymph node lymphocytes induce proliferation and maturation of chronic lymphocytic leukaemia (CLL) B lymphocytes.

An active supernatant (Ly Con A) was prepared by stimulating the normal human lymph node lymphocytes with Concanavalin A (Con A). Peripheral blood lymphocytes (PBL) from 3 healthy subjects and from 8 patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence of Con A and Ly Con A. The latter induced a significant DNA synthesis both in normal and CLL lymphocytes. A proliferative response was still present in CLL after T lymphocytes depletion. The Con A and Ly Con A treatment also induced morphological changes in CLL lymphocytes consistent with plasma cell differentiation. In 3 cases the appearance of cytoplasmic light chains was detected by immunofluorescence. These findings suggest that peripheral blood B lymphocytes from CLL patients can be stimulated to maturation when helper factor(s) released by mitogen activated lymph node lymphocytes are provided.

Antibody-Producing Cells↗

PubMed1984

Rosetting index (E rosettes/mouse rosettes): a simple diagnostic and prognostic value in CLL.

The rosetting index (E rosettes/mouse rosettes) was evaluated in 34 controls, 4 chronic benign lymphocytosis and 28 CLL patients, grouped according to the Rai classification: 6 asymptomatic stage 0 patients (lymphocytosis less than 10,000/mm3) with a rosetting index of 0.35 +/- 0.2; 11 asymptomatic stage 1-2 patients (lymphocytosis 10,000-40,000/mm3) with a rosetting index of 0.19 +/- 0.11; 9 symptomatic stage 3-4 patients (lymphocytosis greater than 40,000/mm3) with a rosetting index of 0.09 +/- 0.09 and 2 T-CLL patients post splenectomy and 4 chronic benign lymphocytosis patients with a rosetting index of 25 +/- 15. The average rosetting index for the controls was 10.0 (range 3.5-54). Student's t test was p less than 0.0001 for groups 1, 2 and 3 and p less than 0.02 for group 4. These results show that the rosetting index is helpful for the characterization of B-CLL in all stages, the rosetting index decreases with the proliferative activity of the disease and could be used as a prognostic factor, and the rosetting index is significantly increased in T-CLL and chronic benign T lymphocytosis thus being useful in differentiating these conditions from the early stage of CLL, when the SmIg is not conclusive of a monoclonal proliferation.

Animals↗

PubMed1984

Heterogeneity of T-lymphocyte chronic lymphatic leukaemia (CLL). Study with conventional surface markers and monoclonal antibodies.

Lymphocyte surface markers (E-SRBC, EAC, EA gamma and SmIg) and monoclonal antibodies (OKT3, OKT4, OKT8 and OKIa) were used to characterise the blood and bone marrow lymphocytes of T-cell CLL (8 patients). The diagnosis of T-cell CLL was made primarily as the majority of blood lymphocytes formed E-SRBC in each patient. Other markers-EAC, EA gamma and SmIg--showed different patterns of association with E-SRBC. These findings considered together described 4 different phenotypes amongst these patients: (a) E+ (3 patients), (b) E+, EAC+ (1 patient), (c) E+, EA gamma + (2 patients), and (d) E+, SmIg+ (2 patients). Similarly, 4 different groups were defined with the help of monoclonal antibodies. Helper T-cell (3 patients) and suppressor T-cell (1 patient) CLL showed predominantly helper T- and suppressor T-lymphocytes respectively. Mixed T-cell CLL (1 patient) comprised an equal proportion of both subpopulations, while the remaining 3 patients, with excess of one or other subpopulations along with a considerable proportion of Ia antigen-bearing lymphocytes, formed the indeterminate cell type CLL.

Adult↗

PubMed1978

Lymphocyte surface immunoglobulin density and immunoglobulin secretion in vitro in chronic lymphocytic leukemia (CLL).

Lymphocyte surface immunoglobulin (SIg) and immunoglobulin (Ig) secretion were studied in 14 patients with chronic lymphocytic leukemia (CLL) and 12 healthy subjects. The determination of SIgM-bearing (SIgM+) cells by immunofluorescent staining and the quantification of SIgM by radioimmunoassay (RIA) permitted the calculation of the SIgM density. In 12 normal subjects the percentage of SIgM+ cells averaged 8% (range 4%-12%) and the SIgM density 10.2 ng antigenic equivalent/10(6) SIgM+ cells (SD 4.3). In 12 patients with CLL the respective figures were 68% (range 35%-90%) and 0.68 ng (SD 0.57). Ig secretion from pokeweed mitogen-stimulated CLL cells was markedly diminished as compared with normal lymphocytes. In coculture experiments CLL cells had no suppressive effect on Ig secretion of normal lymphocytes and normal lymphocytes did not enhance Ig secretion leukemic lymphocytes. These results indicate that the impaired secretory activity of CLL cells results from an intrinsic anomaly of these cells.

Immunoglobulins↗

PubMed1981

Differentiation ability of the CLL lymphocyte: an immature lymphocyte or an abnormal leukemic cell?

The present study is concerned with the patterns of cell differentiation in chronic lymphocytic leukemia. Most cases correspond to the proliferation of a B-cell clone. In contrast to the normal B-lymphocyte, the B-cell CLL lymphocyte is characterized by: (1) very low amounts of monoclonal surface Ig; (2) the presence of receptors for mouse red blood cells; (3) the presence in a high percentage of cases of dual B and T markers. T-cell CLL is a rare event and is defined by a peculiar clinical and hematological picture including the presence of receptors for sheep erythrocytes, the reactivity with anti-T sera, and negative or very low values of terminal transferase. Different studies have conflicted in their findings on the incidence of null-cell CLL; however, these cases appear to be rare. Perhaps more sensitive methods of study must be employed before concluding that the null-cell CLL exists and before establishing its incidence. Even though great progress has been made in the understanding of this disease, two main questions remain unresolved: 1. Does the proliferating clone correspond to an immature B-lymphocyte, or does it merely represent an abnormal leukemic cell? 2. What is the role of T cells in B-cell CLL?

B-Lymphocytes↗

PubMed1982

OT-CLL: a human T cell chronic lymphocytic leukemia that produces IL 2 in high titer.

This report identifies and describes a human T cell chronic lymphocytic leukemia, OT-CLL, which can be triggered by selected mitogens (either PHA or Con A) to produce IL 2 in high titer. Optimal IL 2 production requires culturing OT-CLL cells at 2 to 5 X 10(6)/ml for 24 hr in the presence of 1 to 2% PHA-M. Under these conditions, the titer of IL 2 generated is greater than 20-fold that obtained from conventional sources, e.g., from mitogen-activated tonsillar lymphocytes. Two lines of experimental evidence suggest that the tumor cell product(s) is IL 2. First, in functional assays, suprenatants derived from cultures of PHA-activated OT-CLL cells trigger the proliferation and long-term growth of IL 2-dependent human TCL cells. Second, a partial biochemical purification of the active moiety(ies) derived from OT-CLL demonstrates marked similarity to conventional human IL 2. Thus, the biologically active material(s) precipitates in 50 to 70% saturated (NH4)2 SO4 solutions; elutes from DEAE-Sepharose in the presence of 0.04-0.08 M NaCl; and has an apparent m.w. of approximately 14,000, as determined by Sephadex G-100 gel filtration. In addition, analysis of OT-CLL cells by indirect immunofluorescence, utilizing a panel of monoclonal antibodies, confirms not only that these tumor cells are of T cell lineage but that they display surface antigens that define the normal human peripheral T cell subset subserving helper or inducer function: OKT3+, OKT4+ , OKT8-.

Cell Count↗

PubMed1995

2-Chlorodeoxyadenosine (CdA) for patients with previously untreated chronic lymphocytic leukemia (CLL).

The encouraging therapeutic results attained with the purine analogue CdA in patients with previously treated CLL prompted us to assess its potential in untreated CLL patients. Nineteen patients, 13 males and six females, median age 65 years (range 27-75), with previously untreated CLL were given monthly courses of CdA, 0.12 mg/kg/day as 2-h i.v. infusions for 5 days, until maximum response or excessive toxicity. Five patients with Binet's stage A, 10 with stage B and four with stage C CLL entered the study. After a median of five courses of CdA (range 1-9) nine complete responses (CR = 47%, CI: 24-69%), five partial responses (PR = 26%, CI: 7-46%) and five failures (= 26%, CI: 7-46%) were recorded. In five complete responders and in one partial responder cytofluorometric analysis of blood and/or bone marrow failed to demonstrate a residual clonal B cell population. A search for residual disease by PCR technology and by immunostaining of bone marrow biopsies however disclosed residual leukemic cells in these six cases. Adverse reactions included fever of unknown origin (n = 3), pneumonia (n = 2), herpes simplex infection, herpes zoster, an anal abscess, a cutaneous rash, autoimmune hemolysis and mental disturbance (one patient each). In this small cohort, neither age, stage, blood counts, cytogenetics or pattern of bone marrow infiltration at inclusion were predictive for response. From these preliminary data, we conclude that CdA has remarkable short-term efficacy in patients with previously untreated CLL. However, toxicity is not negligible and long-term benefit from therapy with CdA still has to be established.

Adult↗

PubMedDate not supplied

Fludarabine and prednisone in pretreated and refractory B-chronic lymphocytic leukemia (B-CLL) in advanced stages.

BACKGROUND: The use of fludarabine, an analog of vidarabine with significant lymphocytolytic activity, has provided encouraging results in the treatment of patients with non Hodgkin's lymphoma (NHL) and sometimes in phase II studies of solid tumors and acute leukemias. Fludarabine has also been shown to be effective in B-CLL. Some studies referred results using fludarabine in high-risk untreated or pretreated CLL patients. METHODS: We report treatment results with fludarabine and prednisone in 22 pretreated B-CLL patients in progressive disease, refractory to CHL and other regimens. RESULTS: One patient obtained a complete response (CR), 8 obtained a partial response (PR). Thirteen failed to respond to treatment. Among the partial responders, 1 patient had fatal pneumonia while neutropenic, another died of disease progression. Among the non responders, 7 died of progressive disease, and 3 evolved into high-grade NHL. Three are still alive in disease progression. CONCLUSIONS: We confirm the effectiveness of fludarabine in pretreated and resistant B-CLL, but in the light of the considerable toxicity observed in this series, we believe that the drug would be better employed as a first-line approach to "younger" untreated B-CLL patients.

Adult↗

PubMed1995

Reactivity of monoclonal antibodies OK-CLL (anti-CD5) with peripheral blood cells of patients with B cell lymphoproliferative disorders.

Reactivity of OK-CLL monoclonal antibodies that can identify CD5 antigen on peripheral blood mononuclear cells, was investigated in 172 patients with B cell chronic lymphocytic leukemia (B-CLL) in clinical stages RAI O-I and RAI II-IV and in patients with non-Hodgkin's lymphomas, classified according to the Working formulation into high and low grade histologic type. The OK-CLL reactivity with B-CLLs in the initial (RAI O-I), as well as in advanced stages of disease (RAI II-IV) was significantly higher than in controls. Peripheral blood cells of lymphoma patients, regardless of histological type, showed a much lower values of the CD5 positive population than chronic lymphocytic leukemia (CLL) patients, and a non significant discrepancy between the number of cells stained with anti-CD5 and those stained with other T cell markers. In spite of the showed considerable decrease of CD5 positive cells in CLL patients during therapy, elevated number of this population compared to normal individuals, after chemotherapy, was found. However, in lymphoma patients of both types of malignancies, CD5 positive population increased concomitantly with therapy. These results may suggest that analysis of CD5 antigen expression on peripheral blood cells of patients with B cell lymphoproliferative malignancies may have diagnostic, or, in correlation with some relevant clinical parameters, a potential predictive value in the treatment of those patients.

Adult↗

PubMed1996

Inhibition of apoptotic cell death in B-CLL by interferon gamma correlates with clinical stage.

Apoptosis was evaluated in B cells from 41 patients with B-CLL and 20 healthy aged-matched controls. B cells were cultured with and without gamma-IFN and other cytokines; apoptosis was quantified at regular intervals throughout a 5-day culture period. According to Rai's criteria, 17 patients were classified as good risk, 16 as intermediate and eight as high risk. In vitro, purified B cells from B-CLL patients were evaluated for apoptosis. Maximal apoptosis (44.12%) was observed at day 5 in cells from patients with poor prognosis. The addition of gamma-IFN to the culture media prevented apoptosis in a dose-dependent manner. Maximal inhibition of apoptosis was achieved with 100 IU/ml of gamma-IFN. The degree of inhibition of apoptosis by gamma-IFN was greater in cells from the high-risk group patients than in those from the intermediate and good prognosis group (P < 0.0001). The expression of gamma-IFN receptors in B-CLL cells was evaluated using a MnAb against the extracellular domain of gamma-IFN receptor. After 4 days in culture with gamma-IFN, only cells from the intermediate- and high-risk groups showed an increase in the density of gamma-IFN receptors (P < 0.001). gamma-IFN was not detected in the sera of our study patients. However gamma-IFN was detectable in the media from both normal B cells and B-CLL cells in culture; there was no difference in the amount of gamma-IFN released by cells from the three groups of patients studied. Our results show that in vivo gamma-IFN inhibits apoptosis of B cells from B-CLL patients. The inhibitory effect of gamma-IFN on apoptosis correlates directly with the severity of the disease and this is likely explained by a marked upregulation of gamma-IFN receptors in cells from patients in the high-risk group.

Aged↗

PubMed1997

Genetic factors predisposing to B-CLL and to autoimmune disease in spontaneous murine model.

The frequent occurrence of autoimmune diseases in patients with B cell chronic lymphocytic leukemia (B-CLL) or in their family members suggests the involvement of related predisposing genetic factors in the two distinct disorders. Because the majority of B-CLL is of CD5 B cell type, and because the majority of CD5 B cells produces polyreactive autoantibodies, certain regulatory abnormalities in the proliferation and differentiation of CD5 B cells appear to be involved in B-CLL and autoimmune disease, respectively. In studies using MHC(H-2)-congenic New Zealand mouse strains, NZB(H-2d), NZW(H-2z) and NZB x NZW F1(H-2d/z), we found that while H-2d/z heterozygosity acts as one genetic predisposing element for autoimmune disease, by providing the element for abnormal differentiation of CD5 B cells, the H-2z/z homozygosity serves as one predisposition for B-CLL, by promoting the abnormal proliferation of CD5 B cells. Another non-MHC-linked genes were also involved in the aberrant proliferation of CD5 B cells, as determined by microsatellite DNA analysis. Among these, there was a single dominant NZW locus located on chromosome 6, closely linked to the locus for TNF receptor p55. Hence our mouse model provides an appropriate tool for studying the relationship between genetic factors predisposing to B-CLL and autoimmune diseases.

Aging↗

PubMed1976

Immunocompetent cells in patients with malignant disease. I. The lack of naturally occurring killer cell activity in the unfractionated circulating lymphocytes from patients with chronic lymphocytic leukemia (CLL).

The unfractionated, buffy coat cells of patients with chronic lymphocytic leukemia (CLL) were compared with their counterpart cells from normal volunteers for the capacity to lyse chromium-labeled xenogeneic target cells in vitro. Whereas killer cells were consistently detected in the circulation of normal individuals, no significant numbers of killer cells could be detected in the circulation of CLL patients. It is concluded that either these cells are not present in the circulation of CLL patients or that they are present in small numbers undetectable by this procedure. The possibility that killer cells in CLL patients are diluted by the much larger number of immunoincompetent cells has been ruled out.

Cytotoxicity Tests, Immunologic↗

PubMed2007

Preclinical assessment of curcumin as a potential therapy for B-CLL.

Curcumin, the principle component of the spice turmeric, has been used as an anti-inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B-CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARgamma or NF-kappaB signaling in curcumin-induced apoptosis was examined by cotreatment with a PPARgamma antagonist or EMSA of nuclear NFkappaB complexes. We also examined whether a clinically achievable concentration of curcumin (1 microM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B-CLL cells from 14 patients, curcumin-induced apoptosis with a mean EC(50) of 5.5 microM. In contrast, the EC(50) for whole mononuclear cells from a healthy donor was 21.8 microM. In a 48 hr wash-out time course, curcumin-induced apoptosis was time-dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF-kappaB levels and 1 microM curcumin augmented both vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B-CLL.

3',5'-Cyclic-AMP Phosphodiesterases↗