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At least 73 records · Page 4Linked to original sources
PubMed2002

UCN-01 (7-hydroxystaurosporine) inhibits DNA repair and increases cytotoxicity in normal lymphocytes and chronic lymphocytic leukemia lymphocytes.

Elevated DNA repair processes represent resistance mechanisms to the treatment of malignancies with alkylating agents. Recently, the cell cycle checkpoint abrogator, UCN-01, was reported to inhibit nucleotide excision repair in cell-free systems. We hypothesized that if UCN-01 was combined with DNA-damaging agents, UCN-01 might inhibit the damage repair processes, thereby enhancing cytotoxicity in quiescent cells. Here, we investigated the effect of UCN-01 on DNA repair and viability of quiescent normal lymphocytes and chronic lymphocytic leukemia lymphocytes treated with UV or the cyclophosphamide prodrug 4-hydroperoxycyclophosphamide (4-HC). DNA damage repair kinetics were determined as DNA single strand breaks by the alkaline single cell gel electrophoresis (comet) assay and by [3H]thymidine incorporation. Pretreatment with UCN-01 inhibited DNA repair initiated by UV or 4-HC in normal lymphocytes as well as chronic lymphocytic leukemia lymphocytes in a concentration-dependent manner at clinically relevant levels (50-300 nM). This inhibition was demonstrated by the decreases in incision capability, DNA resynthesis, and in rejoining, suggesting that UCN-01 inhibits the multiple sites of the repair processes. The higher UCN-01 concentration (300 nM) maximized the inhibitory effects and enhanced the UV- or 4-HC-induced cytotoxicity, as determined by annexin V binding or Hoechst 33342 staining. This enhancement was not obtained by the lower concentrations that incompletely inhibited the repair, suggesting the close association between the inhibition of the repair and the enhancement of the cytotoxicity. Our findings suggest that UCN-01 may be a good candidate for combination strategies of cancer treatment.

Alkaloids↗
PubMed1986

Effect of liposomes on lymphocytes: induction of proliferation of B lymphocytes and potentiation of the cytotoxic response of T lymphocytes to alloantigens.

Liposomes of certain lipid composition prepared by the detergent removal method (Brunner, J. et al., Biochim. Biophys. Acta 1976. 455: 322) induced the proliferation of spleen cells from different mouse strains. Spleen cell populations enriched in B lymphocytes and those obtained from nude mice were induced to proliferate, whereas spleen cell fractions enriched in T lymphocytes and thymocytes were not. The mitogenic effect of liposomes resembled that of lipopolysaccharide (LPS) and it depended upon their lipid composition. Liposomes prepared from dimyristoyl lecithin (DML), 2:1 dimyristoyl lecithin:cholesterol (DML:C), 2:1 dioleoyl lecithin: cholesterol (DOL:C), and 2:1 egg yolk lecithin:cholesterol (EYL:C) were mitogenic, whereas liposomes prepared from egg yolk lecithin (EYL) alone were not mitogenic for spleen cells. The mitogenic effects of these liposome preparations were in the decreasing order DML greater than DOL:C greater than or equal to EYL:C greater than DML:C greater than EYL. The results suggest a correlation between the membrane fluidity of liposomes and their mitogenic effect. Although no proliferative response was induced on T lymphocytes, two of these liposomes, DML and EYL:C, had the ability to potentiate the cytotoxic response of T lymphocytes to alloantigens in mixed leukocyte culture. In responder-stimulator combinations which differed for the H-2K, H-2D or the entire H-2 region, these liposomes potentiated the cytotoxic response significantly. The results suggest that liposomes have an ability to modulate T lymphocyte response.

Adjuvants, Immunologic↗
PubMed1975

Lymphocyte abnormalities in Aleutian disease virus infection of mink: decreased T lymphocyte responses and increased B lymphocyte levels in persistent viral infection.

Persistence of virus and a marked hypergammaglobulinemia are consistent features observed in mink with Aleutian disease virus infection. These events may result from altered lymphocyte function in infected mink. To test this possibility we determined the ability of lymphocytes from infected mink to respond to phytolectins (PHA and Con A), and a specific antigen (KLH) in a lymphocyte transformation test and quantitated the number of lymphocytes bearing surface immunoglobulin. Infected mink had a significantly lower response than normal mink to PHA and Con A (P less than 0.025), and the difference in the responses increased progressively with time post-infection. Infected mink immunized with KLH also had a decreased ability to respond to this antigen when compared to normal immunized mink (P less than 0.001). The number of lymphocytes bearing surface immunoglobulin was significantly elevated in three of 10 mink infected for 10 weeks, and in all of seven mink infected 32 weeks (P less than 0.001).

Aleutian Mink Disease↗
PubMed1993

Human colonic intraepithelial lymphocytes suppress in vitro immunoglobulin synthesis by autologous peripheral blood lymphocytes and lamina propria lymphocytes.

Human colonic intraepithelial lymphocytes have been shown to suppress the proliferation of autologous lamina propria lymphocytes and allogeneic peripheral blood mononuclear cells. This study has shown that, in vitro, intraepithelial lymphocytes suppress IgA and total immunoglobulin synthesis (but not IgG or IgM production) by autologous peripheral blood and lamina propria lymphocytes. This down regulation of IgA production is mediated by a soluble factor secreted by the intraepithelial lymphocytes. There is no difference in immunoglobulin down regulation by intraepithelial lymphocytes of control subjects and patients with inflammatory bowel disease.

Adolescent↗
PubMed1991

Functional characterization of tumor-infiltrating lymphocytes, lymph-node lymphocytes and peripheral-blood lymphocytes from patients with breast cancer.

Mononuclear cell infiltration is frequently seen within human solid tumors. Effector cells within the tumor site usually fail to exhibit cytotoxic or natural killer activity when freshly isolated; however, they develop potent and sometimes specific cytotoxicity after expansion in IL2. Thus, local tumor environment may influence lymphocyte function. In our study, we disaggregated human breast-cancer and lymph-node tissue to obtain lymphocyte-enriched cell fractions. Besides phenotypic analysis, functional characterization with regard to proliferation and cytokine production of tumor-infiltrating lymphocytes (TIL), peripheral-blood lymphocytes (PBL) and lymph-node lymphocytes (LNL) was the aim of our study. TIL showed an enrichment of CD8+ cells with a corresponding decrease in CD4+ cells in comparison with PBL and LNL. In response to PHA, TIL showed decreased 3H-thymidine uptake, but TIL were significantly stimulated by rhIL2. TIL produced low levels of IL2, TNF and IFN gamma upon mitogen/phorbol ester stimulation, while PBL produce high levels of TNF and IFN gamma but low levels of IL2. Under the same experimental conditions, LNL produce high levels of TNF and IL2 but low levels of IFN gamma. Mitogen-mediated TNF secretion was increased after addition of autologous tumor cells in TIL and LNL, whereas IFN gamma secretion tended to be suppressed. Our results indicate different patterns of activities of TIL, LNL and PBL from breast-cancer patients.

Breast Neoplasms↗
PubMed1989

Metabolism of peripheral lymphocytes, interleukin-2-activated lymphocytes and tumor-infiltrating lymphocytes from 31P NMR studies.

31P NMR spectra of tumor-infiltrating lymphocytes (TILs) were found to be significantly different from those of normal peripheral lymphocytes. The greatest difference was in the phosphodiester (PDE) region, mainly in the glycerophosphocholine (GPC) signal. Short-term activation of peripheral lymphocytes with interleukin-2 induced a small increase in ATP levels. In all lymphocytes the phosphomonoester (PME) region is dominated by phosphoethanolamine (PE), while there is an unusual absence of phosphocholine (PC). Perfusion of these cells with high concentrations of choline caused only a minimal increase in PC, indicating that choline kinase is not the rate limiting step of lecithin synthesis in lymphocytes.

Adenosine Triphosphate↗
PubMed1977

Responses of alloantigen-primed lymphocytes in vitro. The contribution of increased frequencies of responding lymphocytes to differences between reactivity of normal and primed lymphocyte populations.

Sensitization of lymphocytes against allogeneic cells in vitro results in significant enrichment of alloreactive lymphocytes. Such enrichment was found to profoundly influence the conditions for measuring proliferative responses. Fewer primed lymphocytes than unprimed ones had to be cultured to favor optimal proliferation. Second, proliferative responses could be detected using 10 to 20 times fewer primed responding cells than when using unprimed responders. Finally, although responses of both unprimed and primed lymphocytes were dependent on the number of stimulator cells in culture, the primary mechanism(s) through which this dependence was expressed appeared to differ. The results demonstrate that, under the same conditions, comparisons of responses of two populations that contain different proportions of reactive lymphocytes may not be justified.

Cells, Cultured↗
PubMed1977

Murine B lymphocyte heterogeneity: distribution of complement receptor-bearing and minor lymphocyte-stimulating B lymphocytes among cells with different densities of total surface Ig and IgM.

The distribution of complement receptor-bearing (CR+) and minor lymphocyte-stimulating (Mls)-defined lymphocyte-activating determinants (LAD) among B lymphocytes with different densities of total surface immunoglobulin (sIg) and sIgM was determined. B lymphocytes that bore intermediate densities of sIg and low densities of sIgM had the highest frequency of CR+ cells and were the most active in expressing Mls-defined LAD. The distribution of these and other surface markers on B-lymphocyte subpopulations is discussed.

Animals↗
PubMed1991

Assessment of tumour-infiltrating lymphocytes, regional lymph node lymphocytes and peripheral blood lymphocytes and their reaction to interferon-gamma in patients with renal carcinoma.

The immunological distribution of tumour-infiltrating lymphocytes (TIL), regional lymph node lymphocytes (RLNL) and peripheral blood lymphocytes (PBL) was evaluated by means of immunohistochemical staining using monoclonal antibodies of each subset of lymphocytes (stored in frozen sections) in a series of 22 patients with renal carcinoma. The immunological effect of IFN (interferon)-gamma on these immunocompetent cells was also investigated. The effect of IFN-gamma on TIL was an increase in CD3 (pan-T cells), especially an increase in CD8 (cytotoxic/suppressor-T cells). When examining these cells according to stage and grade, a marked increase in CD3 was found in low stage and low grade patients. With regard to RLNL, there was a tendency towards a decrease in CD3 and an increase in CD20 (B-cells) following the administration of IFN-gamma. No specific effect on stage and grade was observed apart from a reduction in T cell subset ratios in high grade patients. With regard to PBL, no specific trend was noted except for an increase in CD16 (NK cells) when IFN-gamma was administered.

Aged↗
PubMed1985

The autologous mixed lymphocyte reaction in cord blood lymphocytes: altered kinetics and magnitude of proliferative response compared to the adult autologous mixed lymphocyte reaction.

In the autologous mixed lymphocyte reaction (AMLR) T lymphocytes proliferate in response to stimulation by autologous non-T mononuclear cells. The AMLR has characteristics of a cell mediated immune response, and is thus thought to play a role in immune regulation. Cord blood lymphocytes often function differently than do adult lymphocytes. To determine if the AMLR in cord blood differed from that of adults, the kinetics and magnitude of the proliferative response in the AMLR was studied in 20 cord bloods and 14 adults. The magnitude of the AMLR was significantly lower in the cord cells compared to the adult response on all days tested except days 1 and 2. On the first 2 days of culture the cord cells had a higher proliferative response than the adult cells, but this could be accounted for by the high spontaneous proliferation in the cord cells.

Adult↗
PubMed1975

Human lymphocyte surface immunoglobulin capping. Normal characteristics and anomalous behavior of chronic lymphocytic leukemic lymphocytes.

The phenomenon of redistribution of surface membrane immunoglobulin (Ig) components (capping) has been well described in mouse lymphoid cells. The characteristics of this process in human lymphocytes are less clear. This study characterizes the phenomenon of surface membrane Ig redistribution of normal and chronic lymphocytic leukemia (CLL) lymphocytes with the use of fluoroscein-labeled anti-Ig sera. Normal lymphocytes underwent rapid cap formation after incubation with anti-Ig serum in the cold and subsequent rewarming. The morphology was characteristic with aggregation over the pole of the cell opposite the nucleus and over the uropod when present. The process was energy dependent but independent of protein synthesis, and could be inhibited by vincristine, vinblastine, and colchicine but not by cytochalasin B. CLL cells, on the other hand, though showing fluorescent complex aggregation on the surface, rarely demonstrated unidirectional movement of these aggregates to form a cap. Cap formation in these cells could not be stimulated by supplementing the energy source or protein concentration of the medium nor by adding glutamic acid which could partially reverse the vincristine and vinblastine inhibition of normal capping. The failure of agents which inhibit motility to inhibit capping of the normal lymphocytes suggests that active locomotion is not a direct prerequisite for capping. The results also suggest the involvement of microtubules in normal capping and the possibility that abnormal membrane structure or microtubular function could explain the failure of CLL cells to behave normally in this regard. The role of this cellular defect in the immune deficiencies exhibited by many patients with CLL, however, is not established.

Animals↗
PubMed1976

Comparison of normal and chronic lymphocytic leukemia lymphocyte surface Ig determinants using peroxidase-labeled antibodies. II. quantification of light chain determinants in atypical lymphocytic leukemia.

Five cases of atypical lymphocytic leukemia were investigated with regard to their membrane-associated light chains. Detection and quantitation of antigenic determinants were performed by means of peroxidase-labeled antibodies according to Avrameas et al. The cases studied had clinical and cytologic features in common: an active clinical course, marked splenomegaly, severe anemia and thrombocytopenia, little or no lymph node enlargement, and very high white blood counts with small mature lymphocytes and poorly differentiated lymphoid cells. Blood lymphocytes of all patients carried a single type of light chain, and 90%-100% of the cells were stained. The average number of antigenic sites per cell was 72,500 (range 40,000-97,500). These results differed from those previously found in typical CLL (mean value 9000) and approached the values of normal peripheral blood lymphocytes (90,000). The criteria investigated in this study could be of value for the diagnosis and prognosis of some atypical forms of lymphocytic leukemia.

Aged↗
PubMed1981

Mycoplasma-mediated activation of normal mouse lymphocytes: induction of cytotoxic lymphocytes and lymphocyte transformation by Mycoplasma arthritidis are under Ir gene control.

The ability of M. arthritidis, a potent arthritogenic agent, to induce normal unsensitized lymphocytes to undergo blast transformation and to become nonspecifically cytotoxic for syngeneic and allogeneic target fibroblasts was found to be dependent upon the donor strain of mouse. Lymphocytes from CBA (H2k) and BALB/c (H2d) mice were identified as high responders and lymphocytes from C56BL/10 mice (H2b) as low or nonresponders. In the cytotoxicity assay the extent of cell lysis was dependent upon the origin of both the effector cell and the target cell. By comparing the ability of M. arthritidis to activate lymphocytes from various congenic and H-2 recombinant mouse strains we demonstrated that control of the degree of responsiveness was determined by the H2 gene complex. Further studies revealed that the region controlling induction of cytotoxic lymphocytes is located to the right of the I-J subregion and to the left of the D region, most probably the I-E and/or I-C subregions of the major histocompatibility complex. These observations may be of importance in regard to the susceptibility of different mouse strains to the pathogenic effects of M. arthritidis.

Animals↗
PubMed1986

Proliferation of human peripheral blood lymphocytes induced by recombinant human interleukin 2: contribution of large granular lymphocytes and T lymphocytes.

Recombinant human interleukin 2 (rH IL-2) in the presence or absence of additional stimuli, was found to be able to induce and support the proliferation of human peripheral blood lymphocytes (PBLs). These proliferative effects were observed at low doses (less than or equal to 10 U/ml) of interleukin 2 (IL-2) only when additional signals (antigen, mitogen) were provided. However, higher doses (greater than or equal to 100 U/ml) of rH IL-2 significantly stimulated the proliferation of PBL even in the absence of exogenous lectin, antigen, or allogeneic serum. The subpopulation of lymphocytes most responsive to these higher doses of rH IL-2 was the large granular lymphocyte (LGL), the morphologic homologue of natural killer activity. After the separation of human PBLs on discontinuous Percoll gradients, cells from fraction 2 (greater than 90% LGLs) responded in a dose-dependent manner to rH IL-2 alone, whereas cells from fraction 6 (greater than 90% T cells) were only slightly responsive to rH IL-2 alone. A portion of the proliferation of cells from fraction 2 was dependent on the expression of the TAC receptor, because the prior removal of TAC-positive cells significantly reduced IL-2-induced lymphocyte proliferation. These results demonstrate that human LGL that have not been exogenously stimulated can proliferate in direct response to IL-2, and suggest that LGL are the major cellular phenotype in the proliferative response that has been observed clinically.

Cell Cycle↗
PubMed1984

T-lymphocyte and B-lymphocyte dichotomy in anuran amphibians: II. Further investigations on the E-rosetting lymphocyte by using monoclonal antibody azathioprine inhibition and mitogen-induced polyclonal expansion.

We have continued to search for characteristics of T-lymphocytes in anuran amphibians. Inhibition assays using the monoclonal antibodies OKT-11 and T-11, the T-cell immunosuppressive drug azathioprine, and mitogens confirmed the nature of E-rosetting peripheral blood lymphocytes (PBL) in Rana pipiens. Both monoclonal antibodies specifically inhibited E-rosetting in a dose-dependent fashion; absorption of the monoclonals by frog PBL specifically removed inhibition on human E-rosetting T-cells. Lysostripping frog E-receptors with monoclonals and a second FITC antibody revealed a fluorescent lymphocyte population which capped off the receptor as shown by subsequent inhibition of E-rosetting. Significant resynthesis of E-receptors occurred 24 hours after lysostripping, especially in nylon wool effluent fractions. Azathioprine allowed us to define tentatively two subpopulations of E-rosetting lymphocytes: one nylon wool adherent and sensitive to inhibition at low concentrations and another resistant but sensitive to higher (cytotoxic) concentrations of azathioprine. In addition, T-cell but not B-cell mitogens induced expansion of E-rosetting cell populations. Our results support a thymic origin for Rana pipiens' E-rosetting cells. With respect to evolution, human and frog E-receptors are probably homologous, sharing at least one and probably two different antigenic determinants.

Animals↗
PubMed1992

Gamma-interferon enhances the cytotoxic activity of interleukin-2-induced peripheral blood lymphocyte (LAK) cells, tumor infiltrating lymphocytes (TIL), and effusion associated lymphocytes.

The effect of gamma-interferon (IFN-gamma) on the induction of interleukin-2 (IL-2) activated killer cell activity was studied: (I) in peripheral blood lymphocytes (LAK cells) from cancer patients and healthy donors, (II) in lymphocytes infiltrating solid tumors (TIL) from melanoma and breast cancer patients, and (III) in pleural effusion associated lymphocytes (EAL) from patients with lung adenocarcinoma. The coculture of LAK, TIL and pleural effusion mononuclear cells (MNC) with several doses of IFN-gamma (10, 50, 250, and 1250 U/ml) and a low dose of IL-2 (10 U/ml) for 5 days resulted in a synergistic effect on the cytotoxicity of these cells against several tumor cell lines. Furthermore there was a potentiation in the proliferation of MNC after a 5-day culture. The induction of lymphocyte cytotoxicity by a combination of IFN-gamma with low doses of IL-2 may be helpful in designing more effective cancer immunotherapeutic protocols with LAK, TIL or EAL.

Cytotoxicity, Immunologic↗