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L Matera

Publications and source records attributed to L Matera.

At least 37 records · Page 2Linked to original sources
PubMed1996

Role of prolactin in the in vitro development of interleukin-2-driven anti-tumoural lymphokine-activated killer cells.

Exogenous prolactin (PRL) has been shown to synergize with low-dose interleukin-2 (IL-2) and induce the proliferation and lymphokine-activated killer (LAK) maturation of natural killer (NK) cells. PRL itself can also generate LAK activity. Here we show that its local production occurs during, and is necessary for, LAK development. IL-2-stimulated peripheral blood mononuclear cells (PBMC) and purified NK cells were exposed to anti-human (h)PRL antiserum, and residual LAK activity was measured on day 7 against the promyelocytic leukaemia cell line HL-60. Inhibition of LAK activity was much more evident in PBMC compared with NK cell cultures (47% decrease. P - 0.013 and 18.5% decrease. P = 0.048, respectively). Up-modulation of a 32S-methionine-labelled 27,000 MW protein was detected in the lysates and supernatants of IL-2-stimulated PBMC immunoprecipitated with an anti-PRL antiserum. By contrast, the cytoplasmic PRL immunoreactivity observed in freshly isolated NK cells and in IL-2-stimulated, but not unstimulated, NK cell cultures was not associated with PRL gene activation, and can thus be referred to internalized PRL. Preferential re-uptake of externally derived PRL by IL-2-stimulated NK cells was also indicated by up-modulation of the PRL receptor. These data, as a whole, indicate that the PRL promotion of LAK differentiation is mainly mediated by paracrine secretion, with a minor contribution from internalized PRL.

Cell Differentiation↗
PubMed1996

AIDS-related Burkitt's-type lymphomas are a target for lymphokine-activated killers induced by interleukin-2 and prolactin.

The development of non-Hodgkin's lymphomas (NHL) is one of the major complications of AIDS. Although several biologic aspects of AIDS-related NHL have been clarified, their sensitivity to immune system cytotoxic effectors has not been tested. In this study, we have investigated the susceptibility of one major AIDS-related NHL type, Burkitt's-type lymphoma (BL), to the cytotoxic activity of lymphokine-activated killers (LAK) and prolactin-activated killers (PAK), which were generated from peripheral blood mononuclear cells upon stimulation with interleukin-2 (in the case of LAK cells) and prolactin (in the case of PAK cells). The sensitivity of AIDS-related BL to in vitro raised cytotoxic effectors was compared with that of BL variants of the general population, including sporadic BL and endemic BL. The data show that AIDS-related BL is susceptible to cytolysis by LAK cells, whereas both LAK and PAK cells can efficiently kill endemic BL. In contrast, sporadic BL showed resistance to all cytotoxic effectors tested. Intriguingly, in the case of AIDS-related and endemic BL suboptimal doses of interleukin-2 in combination with prolactin displayed a cytotoxic effect similar to that of LAK cells, suggesting a synergistic activity of the two agents. Overall, these data corroborate the notion that the distinct BL variants differ in their biologic features despite their morphologic and genetic similarity.

Burkitt Lymphoma↗
PubMed1995

Regulatory action of prolactin on the in vitro growth of CD34+ve human hemopoietic progenitor cells.

The pituitary hormone prolactin (Prl) is known to act as a local regulator of immune cell function, and Prl-binding receptors (Prl-R) have been described to share distinctive features with the members of the newly described cytokine/hemopoietin receptor superfamily. Here we show that the hormone can functionally interact with lineage-specific hemopoietic factors. When highly purified progenitor cells (CD34+ve) were seeded in semisolid methylcellulose cultures in the presence of interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF), and erythropoietin (Epo), a selective enhancing effect of Prl on the formation of colony forming unit-granulocyte (CFU-G) and burst forming unit-erythroid (BFU-E) colonies was observed. The effect of the hormone was plotted as a bell shaped curve, with the optimal response at the supraphysiological concentration of 50 ng/ml. Limiting dilution analysis showed that Prl acted directly on hemopoietic progenitors. This was confirmed by the observation on the CD34+ve cells of Prl-binding sites reacting with the specific monoclonal antibodies (mAbs), U5 and PrR-7A. Immunoprecipitation of the metabolically labeled CD34+ve cells with the PrR-7A mAb revealed a structure of 43 kD under reducing conditions. Analysis of the early events associated with the Prl/Prl-R interaction showed an increased number of cells engaged in DNA and hemoglobin synthesis. Enhanced erythroid differentiation of CD34+ve cells in the presence of Prl was secondary to upmodulation of receptors for the lineage-specific factor Epo. Together these data demonstrate the existence of a functional interplay between Prl and hemopoietic factors.

Antibodies↗
PubMed1992

Normal development of lymphokine activated killing (LAK) in peripheral blood lymphocytes from hyperprolactinemic patients.

The effect of prolactin on the interleukin 2 (IL2)-driven development of Lymphokine Activated Killing (LAK) by normal PBL and by PBL from hyperprolactinemic patients was investigated. Concentrations of PRL corresponding to the physiological serum levels of the hormone and to the Kd of the PRL receptors on NK cells (6-20 ng/ml, 0.3-1 nM) had no effect on the generation of LAK activity by normal PBL, whereas 100-200 ng/ml were slightly, although significantly, inhibitory. By contrast, PBL from 16 hyperprolactinemic patients developed levels of LAK activity comparable with those generated by PBL from age- and sex-matched normoprolactinemic donors.

Adolescent↗
PubMed1992

Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes.

Prolactin (PRL) has been shown to contribute to the development of lymphoid tissues and maintenance of physiological immune function. Here we show that the role of the hormone extends to the control of the effector phase of the immune response. In addition to triggering resting lymphocytes to cell division, the hormone can also control the magnitude of their response to polyclonal stimuli. Concentrations of PRL in the physiological range increased the [3H]thymidine, [3H]uridine, and [3H]leucine incorporation of unstimulated NK cells cultured in serum-free conditions. The same concentrations of the hormone increased the response of NK, T, and B cells to the mitogenic stimuli interleukin 2 (IL2), phytohemagglutinin (PHA), and staphylococcus aureus cowan, respectively, the effect being maximally evident in the presence of suboptimal concentrations of the mitogens. By contrast concentrations of PRL five- to tenfold the physiological levels inhibited the mitogenic response to IL2 and PHA. These data indicate a double-faceted regulatory role of this hormone in vivo.

B-Lymphocytes↗
PubMed1992

Effect of human interleukin 3 on the susceptibility of fresh leukemia cells to interleukin-2-induced lymphokine activated killing activity.

Pretreatment of acute myeloblastic leukemia cells with the hemopoietic growth factor interleukin 3 (IL3) increased their susceptibility to lymphokine activated killing (LAK) but did not affect their constitutive resistance to native natural killer activity. In addition, IL3 treatment did not alter the LAK cell-mediated killing of CD34+ hemopoietic progenitors present in normal bone marrow. Increased 3H-thymidine uptake was generally observed after IL3 treatment. However, failure to proliferate in response to IL3, observed in some cases, did not prevent changes in LAK susceptibility. Enhanced lysis of IL3-treated leukemic cells was accompanied by a moderate increase of the effector-target binding. Increased LAK susceptibility was already observed at 18 h, while optimal cytolysis and expression of the cell adhesion molecule (CAM) LFA-3 (CD58) by IL3-treated AML cells were concomitantly observed at later culture times. In contrast, the CAM ICAM-1 (CD54) was not modulated by IL3, nor were significant changes in the expression of either CAMs observed in normal hemopoietic cells. Blocking experiments with the anti-CD58 monoclonal antibody demonstrated a variable neutralizing effect on the IL3-induced increase of LAK activity, depending on the leukemia cell studied. The effect described here, together with the known role of IL3 in normal hemopoiesis makes it a factor of potential therapeutic value for the treatment of leukemic patients.

Antigens, CD↗
PubMed1992

Synthesis of a prolactin-like peptide by natural killer cells: positive regulation by CD16 and exogenous prolactin.

We have previously shown that Prolactin (PRL) activates the native and the in vitro acquired cytotoxicity and the DNA synthetic activity of Natural Killer (NK) cells. Here we show that the supernatant and the cell lysate of NK cells express a 35S-labelled 50 kDa peptide specifically immunostained by two different PRL-antisera. The supernatant of NK cells was biologically active in a Nb2 assay and the activity could be adsorbed by an anti-PRL antiserum. The production of the PRL-like peptide only occurred when NK cells were isolated through binding to immobilized immunocomplexes, the biological ligand for CD16, and was positively modulated by exogenous PRL. These results indicate that PRL, produced by NK cells following stimulation, may act in an autocrine fashion to maintain and/or activate the NK cell function.

Antigen-Antibody Complex↗
PubMed1991

Effect of human alpha-fetoprotein on native and in vitro-stimulated NK activity.

We have examined the effect of human alpha-fetoprotein (h-alpha FP), at concentrations ranging from the physiological to pathological circulating levels, on the native and alpha IFN- and IL2-boosted NK activity of normal peripheral blood lymphocytes (PBL). The cytotoxic function of unstimulated PBL was unchanged after a 16 hr incubation with 200 to 8000 ng/ml h-alpha FP. By contrast, this treatment significantly reduced the responsiveness of PBL to the NK-enhancer factors IFN and Interleukin 2. Optimal inhibition was observed when cells were pre-incubated with h-alpha FP before being stimulated with IFN. The sensitivity of PBL to the h-alpha FP mediated inhibition was restricted to the very early times (30 min) of incubation with the stimulating agents.

Cytotoxicity, Immunologic↗
PubMed1990

Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors.

The capacity to generate lymphokine-activated killer (LAK) cells and the susceptibility of the neoplastic cells to both allogeneic and autologous LAK effectors were studied in B and T chronic lymphoproliferative disorders. While in B-cell chronic lymphocytic leukemia (B-CLL) the depressed natural killer function could be restored after a 7-day incubation with recombinant interleukin (IL-2), B-CLL mononuclear cells showed a reduced LAK activity compared with normal LAK cells. Furthermore, in all but 1 of the 20 B-CLL samples tested the leukemic cells were totally resistant to autologous LAK effectors. In most cases the leukemic cells were also resistant to normal allogeneic LAK cells. Competition experiments demonstrated that the patients' LAK cells, as well as normal LAK effectors, were capable of recognizing B-CLL cells, pointing, therefore, to a postbinding cytolytic defect. In hairy cell leukemia (HCL) an overall reduced LAK activity against allogeneic targets was documented, but, at variance from B-CLL, hairy cells were often susceptible to the lytic effect of normal LAK cells, and in half of the cases tested the neoplastic population was also sensitive in an autologous system. Similarly to B-CLL, in the great majority of T chronic lymphoproliferative disorders studied, the pathologic cells were resistant to normal and autologous LAK effectors and a defective LAK generation was found. These results demonstrate that in most B and T chronic leukemias the LAK function is defective and, when inducible, does not appear directed against the leukemic population. The possibility of exploiting an immunotherapeutic approach with IL-2/LAK cells in the management of chronic lymphoproliferative disorders does not gain support by these findings.

Cells, Cultured↗
PubMed1989

B cells from chronic lymphocytic leukemia (CLL) patients are strong inducers of proliferation and major histocompatibility complex (MHC)-unrestricted [natural killer (NK)-like] cytotoxicity in normal T-lymphocytes.

We studied the ability of chronic lymphocytic leukemia (CLL) B cells to stimulate proliferation and major histocompatibility complex (MHC)-unrestricted [natural killer (NK)-like] cytotoxicity in a mixed lymphocyte tumor-cell culture (MLTC). CLL-derived B cells induced a significantly higher proliferative response than did B cells from healthy normal donors. Comparable levels of interferon and interleukin-2 production were detected in the mixed lymphocyte cultures (MLC) set up with normal B cells from healthy donors and in MLTC. Higher levels of NK-like cytotoxic activity were induced after stimulation with CLL than with normal B cells in nonlytic precursors. Inhibition experiments with specific monoclonal antibodies indicate that the NK-like response in MLTC is attributable to HLA class II antigens, which are expressed at comparable levels on CLL and normal B cells. Percoll gradient centrifugation of the MLC and MLTC recovered cells demonstrated that the NK-like effectors in both types of cultures were blast-transformed, highly mitotic cells.

B-Lymphocytes↗
PubMed1989

Effect of two aliphatic aldehydes, methylglyoxal and 4-hydroxypentenal, on the growth of Yoshida ascites hepatoma AH-130.

The influence of a ketoaldehyde, methylglyoxal (MG), and a hydroxyalkenal, 4-hydroxypentenal (HPE), on the growth of a highly-deviated tumour has been investigated. MG and HPE, administered intraperitoneally, strongly depressed in rats the proliferative activity of the Yoshida ascites hepatoma AH-130, reducing its mitotic and labelling indices as well as the proportion of cycling cells (growth fraction). Monitoring the effects on the cell cycle by the labelled mitoses method showed that the percentage of labelled mitoses was markedly lowered after either aldehyde, which is indicative for a blocking effect in the S phase. In addition, the mean cell cycle time was slightly prolonged by MG, probably due to accumulation of cells in G1, whereas HPE delayed the first mitotic peak and increased the mean DNA synthetic period without modifying the overall cycle time. The effects of HPE on the cell cycle were prevented by pretreatment with polyamines. Repeated doses of MG significantly increased the fraction of tumour-bearing rats surviving at 90 days ('indefinite' survivors) as well as the survival time of those which succumbed, implying that the carcinostatic effect of MG persisted over several cell cycles. By contrast, HPE did not significantly modify the survival of AH-130-bearing rats, suggesting that its influence on tumour growth was rapidly reversible.

Aldehydes↗
PubMed1989

Biological and molecular evidence for the production of IL-6 by human natural killer cells in culture.

As several of the biological functions of NK cells are similar to the biological effects of IL-6, we tested for the production of this cytokine by cultured NK cells. Conditioned medium from the NK cells supported the proliferation of an IL-6 dependent human leukemic plasma cell line in dose-dependent fashion and this response was abolished by a neutralizing anti-IL-6 serum. Analysis of the mRNA from the NK cell cultures by RNA blotting demonstrated a specific transcript for IL-6 providing further confirmation that these cells elaborate this factor in culture.

Blotting, Northern↗
PubMed1989

Production of colony-stimulating activity by human natural killer cells: analysis of the conditions that influence the release and detection of colony-stimulating activity.

Highly purified natural killer (NK) cell suspensions were tested for their capacity to release colony-stimulating activity (CSA) in vitro. NK cell suspensions comprised primarily CD16+ cells and were devoid of CD3+ T cells, CD15+ monocytes, and of B cells. CSA was detected in the NK cell supernatants and sustained the growth of myeloid colonies from both normal peripheral blood and bone marrow. CSA could be in part inhibited by pretreating NK cell culture supernatants with a specific goat anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antiserum. The inhibition, however, was never complete, a finding that suggests that additional factors were responsible for CSA. Incubation of NK cells with K562 cells (an NK-sensitive target) or with normal bone marrow cells resulted in the appearance of a strong colony-inhibiting activity (CIA) in the culture supernatants. Such CIA was demonstrable in an experimental system where bone marrow or peripheral blood progenitors were induced to form myeloid colonies in the presence of conditioned medium by CSA-producing giant cell tumor (GCT) cells. Stimulation of NK cells with NK-insensitive targets failed to induce CIA production. Neutralizing antitumor necrosis factor (TNF) monoclonal antibodies (MoAbs) were found capable of inhibiting CIA present in the supernatants of NK cells stimulated with K562 cells. Following treatment with anti-TNF antibodies, CSA was again detectable in the same supernatants. This finding indicates that induction of TNF production did not concomitantly switch off CSA production by NK cells. Pretreatment of NK cells with recombinant interleukin-2 (rIL-2) or gamma interferon (r gamma IFN) did not change the amount of CSA released. However, treatment with rIL-2 caused the appearance of a factor in the NK cell supernatants capable of sustaining the formation of colonies of a larger size.

Antigens, Differentiation↗
PubMed1989

Lymphokine activated killer (LAK) activity in lymphoproliferative disorders.

Lymphokine activated killer (LAK) cells are being considered as a new and promising form of immunotherapy in the management of patients with solid tumours. Few informations are instead available on these cytotoxic effectors in haematological neoplasias. Here we shall discuss the possible role of LAK cells in human leukaemias. Evidence will be provided for a rationale in the clinical exploitment of Interleukin 2 (IL2)/LAK cells in the treatment of acute leukaemia patients, whilst the implication of these cytotoxic populations appears more uncertain in chronic lymphoproliferative disorders.

Cytotoxicity, Immunologic↗
PubMed1988

Prolactin receptors on large granular lymphocytes: dual regulation by cyclosporin A.

Although evidence has been provided for a modulatory role of prolactin (PRL) on humoral and cell-mediated immune responses and PRL receptors have been found on T and B lymphocytes, no indications exist concerning the influence of PRL on natural killer (NK) activity nor has a structural basis for interaction been found on the NK effector cells (large granular lymphocytes, LGL). We show here that highly purified LGL express binding sites for PRL. The calculated receptor number was 660 per cell and the dissociation constant (Kd) was 3.0 X 10(-10) M. Since previous studies have reported that cyclosporin (CsA), an immunosuppressive agent used in organ transplant patients, affects the binding of PRL to T and B lymphocytes, but not to rabbit mammary gland cells, we investigated whether this compound could alter the binding of the hormone to LGL. At concentrations from 10(-7) to 10(-6), corresponding to the therapeutical range, CsA induced a complete inhibition of the PRL binding. By contrast, concentrations of CsA ranging from 10(-11) to 10(-9) increased the PRL binding to more than 100% of control levels. In addition to their antitumor role, LGL have been proposed to participate in graft versus host disease and in transplant rejection. The finding that CsA can differently affect PRL-receptor expression on LGL points to an involvement of CsA--PRL interactions in determining the output of these immune responses. In addition, these data strongly support the idea of a close relationship between the neuroendocrine and immune systems.

Binding, Competitive↗
PubMed1988

In vitro and in vivo susceptibility of human leukemic cells to lymphokine activated killer activity.

The susceptibility of human myeloid and lymphoid leukemic blasts to the lytic action of recombinant interleukin-2 (rIL-2)-generated lymphokine activated killer (LAK) cells was analyzed. With the exception of the K562 cell line, all 9 leukemic cell lines tested were resistant to the natural killer activity of freshly isolated peripheral blood lymphocytes (PBL) from healthy donors but were susceptible to the lytic action of PBL cultured for 3 days in the presence of rIL-2. Of the 32 primary myeloid and lymphoid acute leukemia samples investigated, the great majority were natural killer cell-resistant but were variably sensitive to LAK effectors. Variations in LAK activity were observed according to the donor of PBL, while little or no difference was documented in the capacity to elicit LAK activity of PBL cultured with 100 or 1,000 U of rIL-2/ml. Pretreatment of the leukemic target cells with neuraminidase did not increase substantially their sensitivity to LAK activity. LAK cells generated from the PBL of patients at the onset of the disease or in complete clinicohematological remission lysed Raji cells as efficiently as normal LAK effectors. Finally, LAK cells were capable of abrogating the tumor growth in nude mice of a human leukemic T cell line. These findings demonstrate the susceptibility in vitro and in vivo of human leukemic blasts to the lytic effect of LAK cells and point to a possible clinical exploitment of this new form of adoptive immunotherapy in the management of acute leukemia.

Animals↗