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Biomedical subjects

K Hellstrand

Publications and source records attributed to K Hellstrand.

At least 55 records · Page 3Linked to original sources
PubMed1994

Histamine in immunotherapy of advanced melanoma: a pilot study.

Sixteen patients with advanced metastatic malignant melanoma were treated with a high-dose infusion of interleukin-2 (IL-2; 18 x 10(6) IU/m-2 day-1) together with daily subcutaneous (s.c.) injections of interferon alpha (IFN alpha; 3 x 10(6) U/m-2 day-1) in 5-day cycles. Nine of these patients were given histamine (1 mg s.c.) twice daily during treatment with IL-2 and IFN alpha. In the seven patients who did not receive histamine, one partial response (that is a reduction of more than 50% in the total tumour burden) was observed in a patient with skin and lymph node melanoma. In the eight histamine-treated patients evaluable for response, four partial responses were observed. Two other patients showed regression at one site of metastasis but tumours remained unchanged at other sites. Two histamine-treated patients showed complete resolution of extensive liver metastasis. Sites of response in histamine-treated patients also included the subcutis, lymph nodes, skeleton, spleen and muscle. Lung melanoma did not respond to histamine/IL-2/IFN alpha. Three patients with lung tumours responded with significant (more than 50%) reduction of the volume of soft-tissue tumours, suggesting that the response to histamine may be organotropic. Survival was significantly prolonged in patients receiving histamine. Our data suggest that treatment with histamine may improve the antitumour efficacy of immunotherapy in metastatic melanoma.

Adult↗
PubMed1993

5-Propyl-2-deoxyuridine induced interference with glycosylation in herpes simplex virus infected cells. Nature of PdU-induced modifications of N-linked glycans.

In herpes simplex virus-infected (HSV) cells, the antiviral nucleoside analogue 5-n-propyl-2'-deoxyuridine (PdU) may, under certain circumstances, induce a pattern of interference with late steps in formation of N-linked glycans, resulting in increased availability of viral glycoproteins for neutralizing antibodies. The PdU-induced changes in N-linked glycans, released by pronase digestion of the HSV-specified glycoprotein gC-1, were investigated by using lectin affinity chromatography and Bio-Gel P6 gel filtration of glycans, radiolabelled with [3H]galactose or [3H]glucosamine. PdU-treatment of HSV-infected cells totally inhibited addition of sialic acid and reduced the amount of galactose incorporated into N-linked glycans by 70%. In addition, the PDU-treatment caused a decrease in oligosaccharides with affinity for Phaseoulus vulgaris leuco-agglutinin and erythro-agglutinin, and an increase in Lens culinaris lectin (LCA)-binding oligosaccharides, suggesting a PdU-induced shift from multi-branched to moderately branched structures. This shift was also found in HSV-infected B16 mouse melanoma cells, where the large content of multi-branched oligosaccharides contributes to the metastatic potential. The LCA-binding glycans from PdU-treated cells were smaller and contained less galactose units than corresponding structures from untreated cells. In a cell-free system, PdU 5'-monophosphate inhibited the translocation of UDP-GlcNAc, and, to a smaller extent, also the translocation of UDP-galactose into Golgi vesicles, suggesting that nucleotide sugar translocation is one important target for the PdU-induced interference with glycosylation in HSV-infected cells.

Agglutinins↗
PubMed1993

Role of serotonin in the regulation of interferon-gamma production by human natural killer cells.

Monocytes, recovered directly from peripheral blood by counter-current centrifugal elutriation (CCE), were shown to provide two regulatory signals for induction of interferon-gamma (IFN-gamma) in natural killer (NK) cells in response to interleukin-2 (IL-2): an upregulating signal and an inhibitory signal. The inhibitory signal was time-dependent, irreversible, and operating on a pretranslational level, as indicated by the inability of enriched NK cells to accumulate IFN-gamma mRNA in the presence of elutriated monocytes. Monocyte-induced inhibition of IFN-gamma production was abrogated by the biogenic amine serotonin, acting via the 5-hydroxytryptamine, or serotonin (5-HT1A), subset of serotonin receptors (5-HTR). Thereby, serotonin effectively promoted IFN-gamma production in the presence of monocytes. We conclude that serotonergic 5-HT1A receptors transduce signals that are required for NK cells to produce IFN-gamma in response to IL-2.

Cell Communication↗
PubMed1993

Serotonergic 5-HT1A receptors regulate a cell contact-mediated interaction between natural killer cells and monocytes.

Autologous monocytes irreversibly suppressed functions of human natural killer (NK) cells including baseline and lymphokine-induced cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and interleukin-2 (IL-2)-induced proliferation. The suppression of these NK-cell functions was cell contact-dependent and could be evoked only by purified monocytes, recovered directly from peripheral blood by countercurrent centrifugal elutriation (CCE). The presence of monocytes also induced the disappearance of CD16 and CD56 antigen on CD3- NK cells (CD3-/16+/56+-->CD3-/16-/56-). By contrast, T-cell proliferation and the expression of CD3 on CD56- T cells were not susceptible to cell contact-mediated suppression by monocytes. The biogenic amine serotonin abrogated monocyte-induced suppression of NK-cell functions as well as down-modulation of CD16/56 NK-cell antigen. Serotonin thus markedly augmented baseline and lymphokine-induced NK-cell cytotoxicity, ADCC, and NK-cell proliferation, and maintained the expression of NK-cell surface antigens in the presence of elutriated monocytes. The effect of serotonin was mediated by 5-HT1A-type serotonin receptors (5-HT1AR) as indicated by mimicry exerted by 5-HT1AR agonists such as 8-OH-DPAT and (+)-ALK, partial antagonism by the 5-HT1AR antagonists pindolol and cyproheptadine, and lack of antagonism by the 5-HT2R antagonist ketanserin or the 5-HT3R antagonist ondansetron. Our data are suggestive of a cell-to-cell-mediated mechanism by which monocytes down-modulate NK-cell function and phenotype and its serotonergic regulation.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1992

Regulation of the natural killer cell response to interferon-alpha by biogenic amines.

Monocytes, recovered from human peripheral blood by counter-current centrifugal elutriation (CCE), suppressed baseline natural killer (NK) cell cytotoxicity (NKCC) and rendered NK cells resistant to activation of cytotoxicity by human recombinant interferon-alpha (IFN-alpha) by a cell contact-dependent mechanism. Monocyte-induced suppression of resting and IFN-activated NK cells was abrogated by the biogenic amines histamine [via H2-type receptors (H2R)] and serotonin [via 5-HT1A-type receptors (5-HT1AR)]. Our data are suggestive of a monocyte/NK cell interaction that is subject to regulation by biogenic amines.

Cell Adhesion↗
PubMed1991

Monocyte-induced down-modulation of CD16 and CD56 antigens on human natural killer cells and its regulation by histamine H2-receptors.

Human natural killer (NK) cells carry CD16/FcR and CD56 cell-surface Ag but lack the T-cell marker CD3. Here we show that incubation of resting human NK cells with CD3-/16+/56+ phenotype with autologous monocytes induced the disappearance of CD16 and CD56 cell-surface Ag on NK-cells but did not affect CD2 or CD3 Ag expression on T-cells. Monocyte-induced down-modulation of NK-cell-surface Ag was cell-contact dependent and induced only by freshly isolated monocytes, recovered from peripheral blood by counter-current centrifugal elutriation. Adherence of monocytes abrogated the capacity to induce down-modulation of NK-cell-surface Ag. The biogenic amine histamine dose-dependently reversed the monocyte-induced down-modulation of CD16 and CD56 on CD3- NK-cells. The effect of histamine was mediated by H2-type receptors on monocytes. The data presented are suggestive of a cell-cell-mediated interaction between monocytes and NK-cells which modulates surface expression of NK-cell Ag and its histaminergic regulation.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1991

Cell-to-cell mediated inhibition of natural killer cell proliferation by monocytes and its regulation by histamine H2-receptors.

Human peripheral blood monocytes, recovered by counter-current centrifugal elutriation, suppressed interleukin-2 (IL-2)-induced proliferation of autologous lymphocytes, recovered from low density Percoll fractions. Cell sorting experiments, analysis of phenotype of proliferating cells, and removal of defined cellular subsets by complement cytotoxicity revealed that IL-2-induced proliferation was confined to CD3-/16+/56+ natural killer (NK) cells. Monocyte-induced suppression of NK-cell proliferation was completed within 1 h of incubation with monocytes and unrelated to the formation of prostaglandins or other intermediary factors. The biogenic amine histamine, acting via H2-type histamine receptors (H2R) on monocytes, completely counteracted the monocyte-mediated suppression of IL-2-induced NK-cell proliferation. Our data are suggestive of a H2R-regulated, cell-cell-mediated mechanism by which monocytes down-modulate NK-cell proliferation.

Antigens, Differentiation↗
PubMed1990

Role of histamine in natural killer cell-mediated resistance against tumor cells.

The formation of lung metastases by i.v.-injected B16 melanoma (F1 and F10 strain) cells in Swiss albino, C57BL/6, and BALB/c mice was reduced by a single dose of histamine given 24 h before tumor cell inoculation. The antimetastatic effect of histamine was specifically mediated by histamine H2-receptors (H2R): it was blocked by the H2R antagonist ranitidine and mimicked by dimaprit, a specific H2R agonist but not by an H2R-inactive structural analog of this compound, nor-dimaprit, or the H1R agonist 2-thiazolyl-ethylamide. A single dose of any of the H2R antagonists ranitidine, tiotidine, famotidine, or cimetidine drastically augmented metastasis. Effects of H2R-interactive compounds on B16 metastasis required intact NK cells, as judged by the inability of histamine or ranitidine to affect B16 metastasis after NK cell depletion in vivo using antibodies to asialo-GM1. NK-cell-mediated lysis of YAC-1 lymphoma cells in vivo was enhanced by histamine and reduced by ranitidine within 4 h after inoculation of tumor cells. The antimetastatic effect of IL-2 was potentiated by histamine; in some experiments, combined treatment with a low dose of IL-2 (6000 U/kg) and histamine completely eliminated metastasis, whereas concomitant treatment with ranitidine abrogated antimetastatic effects of IL-2; animals treated with ranitidine and IL-2 displayed the same level of enhanced metastasis as those treated with ranitidine alone. The presented data are suggestive of an earlier unrecognized role for histamine in NK cell-mediated resistance against metastatic tumor cells.

Animals↗
PubMed1990

Enhancement of human natural killer cell cytotoxicity by serotonin: role of non-T/CD16+ NK cells, accessory monocytes, and 5-HT1A receptors.

Serotonin (10(-4) - 10(-7) M) augmented natural killer cell cytotoxicity (NKCC) of human CD16+/non-T lymphocytes in vitro against the NK-sensitive target cells K 562 erythroleukemic, Molt-4 lymphoma, Chang liver cells, and against EBV-transformed Daudi B-lymphoblastoid target cells by a mechanism of action involving a prostaglandin-and IL-1-independent accessory function of monocytes. No evidence for the production of intermediary, NK-enhancing cytokines by serotonin was obtained, suggesting a cell-to-cell-mediated interaction between monocytes and NK cells as a plausible mechanism of action for the NK-augmenting effect. Monocytes recovered by counter-current centrifugal elutriation but not monocytes recovered by adherence reconstituted the effect of serotonin when added to nonadherent NK cells. NK-enhancing effects of serotonin were mimicked by two 5-HT1A-type serotonin receptor agonists, 8-OH-DPAT and (+)-ALK. The development of NKCC in response to serotonin could be resolved into (i) an induction phase, dependent on the presence of accessory monocytes and serotonin, and (ii) an effector phase, independent of the presence of monocytes or serotonin. Serotonin-activated MNC continued to exert augmented cytotoxicity for at least 8 hr after the removal of serotonin and monocytes. In several experiments, serotonin-activated NK cells killed greater than 75% of K 562 target cells even at low effector to target cell ratios and low baseline NKCC. We suggest that serotonin may have a role in nonspecific tumor defence by regulating an earlier unrecognized interplay between monocytes and NK cells.

Antigens, Differentiation↗
PubMed1990

A cell-to-cell mediated interaction involving monocytes and non-T/CD16+ natural killer (NK) cells is required for histamine H2-receptor-mediated NK-cell activation.

Histamine (10(-4) to 10(-7) M) augmented natural killer cell cytotoxicity (NKCC) of human CD16+, non-T lymphocytes in vitro against the NK-sensitive target cells K562 erythroleukaemic, Molt-4 lymphoma, Chang liver cells and against Epstein-Barr virus (EBV)-transformed, NK-insensitive Daudi B-lymphoblastoid target cells by a mechanism of action involving a prostaglandin- and interleukin 1 (IL-1)-independent accessory function of monocytes. No evidence for the production of intermediary, NK-enhancing cytokines by histamine was obtained, indicating a cell-to-cell mediated interaction between monocytes and NK cells as a plausible mechanism of action for the NK-augmenting effect. Monocytes recovered by countercurrent centrifugal elutriation (CCE), but not monocytes recovered by adherence, reconstituted the effect of histamine when added to non-adherent NK cells. The development of NKCC in response to histamine was time-dependent with (i) an induction phase, dependent on the presence of accessory monocytes and ongoing histamine H2-receptor activation (half-maximal response required approximately 30 min treatment of large granular lymphocyte (LGL)-enriched lymphocytes and monocytes with histamine), and (ii) an effector phase, independent of the presence of monocytes or histamine receptor activation. Histamine-activated mononuclear cells (MNC) continued to exert augmented cytotoxicity for at least 8 h after removal of histamine and monocytes. In several experiments, histamine-activated NK-effector cells killed greater than 90% of the target cells at low baseline NKCC. We suggest that histamine may have a role in non-specific tumour defence by regulating an earlier unrecognized interplay between monocytes and NK cells.

Antigens, Differentiation↗
PubMed1990

Monocyte-mediated suppression of IL-2-induced NK-cell activation. Regulation by 5-HT1A-type serotonin receptors.

In the present study, the effects of serotonin on human natural killer (NK)-cell responsiveness to interleukin 2 (IL-2) was investigated. Concomitant treatment of human lymphocytes, enriched for NK effector cells by Percoll density-gradient centrifugation, with serotonin and IL-2 yielded a synergistic activation of NK-cell cytotoxicity (NKCC) in the presence but not in the absence of monocytes. The monocyte-dependent, regulatory effects of serotonin and/or IL-2 were prostaglandin-independent and could be reconstituted when monocytes, recovered by countercurrent centrifugal elutriation (CCE), were added to purified NK effector cells. The effects of serotonin on baseline and IL-2-activated NK cells were mimicked by the 5-HT1A receptor-specific agonists 8-OH-DPAT and (+)-ALK. Our data suggest that serotonin regulates NK-cell responsiveness to IL-2 via 5-HT1A receptors.

Cell Separation↗
PubMed1990

Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2.

Interleukin-2 (IL-2) is recognized as a major activating signal for human natural killer (NK) cells. The presence of monocytes alters NK cell responsiveness to IL-2. Thus, while IL-2 effectively augments NK cell cytotoxicity (NKCC) in monocyte-depleted NK effector cells, it is relatively ineffective or even suppressive for NK cells in monocyte-containing, NK-cell-enriched mononuclear cell fractions. Here we report that concomitant treatment with IL-2 and the biogenic amine histamine synergistically augmented NKCC against K562 and Daudi target cells of CD3-/CD16+ human NK cells in the presence but not in the absence of monocytes. Addition of peripheral-blood monocytes, recovered by countercurrent centrifugal elutriation, to purified NK cells abrogated IL-2 induced NK cell activation, reconstituted the synergistic, NK-activating effects of histamine and IL-2, and strongly reduced baseline NKCC. The effects of histamine on baseline NKCC and on NK cell responsiveness to IL-2 were related to counteraction of monocyte-mediated NK cell suppression. By contrast, histamine did not affect baseline or IL-2-induced NKCC in mixtures of NK cells and monocytes when the latter cells were recovered after adherence. The effect of histamine on NK cell responsiveness to IL-2 was mediated by H2-type histamine receptors, as judged by mimicry exerted by the specific H2 receptor agonist dimaprit, but not by an H2-receptor-inactive derivative of this compound, N-methyldimaprit, and blocking by the H2 receptor antagonist ranitidine. Experiments in which monocytes and nonadherent NK cells were separately pretreated with ranitidine prior to histamine treatment suggested that NK-regulatory effects of histamine were mediated by H2 receptors on monocytes. Our data suggest that histamine may provide an important signal in the regulation of NK cell responsiveness to IL-2.

Antigens, Differentiation↗
PubMed1989

An immunopharmacological analysis of adrenaline-induced suppression of human natural killer cell cytotoxicity.

The circulating catecholamine adrenaline effectively suppressed human natural killer cell cytotoxicity (NKCC) when added to mixtures of effector lymphocytes and 51Cr-labelled target cells in a 4-hour 51Cr release assay in vitro. The effect was mimicked by the beta 2-receptor agonist terbutaline but not by the beta 1-receptor agonist prenalterol or the alpha 1/alpha 2-receptor agonist clonidine. Adrenaline-induced NKCC suppression was completely and potently antagonized by the mixed beta 1/beta 2-receptor antagonist propranolol and the selective beta 2-receptor antagonist ICI 118,551 but not by the beta 1-selective antagonist metoprolol. By comparing the adrenaline sensitivity of high-density (HD) and low-density (LD) lymphocytes, fractionated by Percoll density gradient centrifugation, we found that HD cells appeared more sensitive to adrenaline-induced suppression than LD cells. In both types of effector cells, adrenaline significantly suppressed NKCC at a final concentration of 10(-11) M. Pretreatment of LD effector cells with IFN-alpha reduced the NKCC suppression by subsequent adrenaline treatment. Pretreatment with recombinant IL-2 virtually abolished the response to adrenaline. This effect was noted also when IL-2 and adrenaline were incubated simultaneously during the 4-hour 51Cr release assay. Our data suggest a role for adrenaline, via lymphocyte beta 2-receptor activation, in the regulation of natural killer cells.

Adrenergic beta-Agonists↗
PubMed1989

Interleukin-2 can induce suppression of human natural killer cell cytotoxicity.

By interaction with monocytes, interleukin-2 (IL-2) suppressed natural killer (NK) cell cytotoxicity (NKCC) of human, Percoll-fractionated, low-density mononuclear cells. The NK-suppressive effect of IL-2 was independent of de novo formation of prostaglandins or protein since it was unaffected by treatment with indomethacin and cycloheximide, respectively. A monoclonal antibody to the p55 (beta) moiety of the IL-2 receptor (anti-Tac/anti-CD25) blocked IL-2-induced NKCC suppression but did not affect the NK-enhancing effect of the lymphokine. We conclude that IL-2 exerts a monocyte-dependent, IL-2 beta-receptor mediated suppressive influence on human NK cells.

Cyclooxygenase Inhibitors↗
PubMed1987

Role of serotonin in the regulation of human natural killer cell cytotoxicity.

Addition of serotonin to mixtures of target cells and natural killer (NK)-enriched human mononuclear cells (MNC) in a 4-hr 51Cr-release assay strongly augmented NK cell cytotoxicity (NKCC) vs K562, Chang, or Molt-4 target cells. The effect was dose dependent at serotonin concentrations of 10(-4) to 10(-7) M, expressed at several effector to target cell ratios, and required the presence of accessory monocytes. A 5-HT1-specific receptor agonist, 8-OH-DPAT, mimicked the enhancing properties of serotonin with similar potency. Equimolar concentrations of the mixed 5-HT1/5-HT2 receptor antagonist cyproheptadine, but not the 5-HT2-specific antagonist ketanserin, completely blocked the serotonin-induced NKCC enhancement. Monocyte/NK cell mixtures incubated with serotonin for 1 hr produced a soluble factor that could enhance the cytotoxicity of autologous, NK-enriched cells depleted of monocytes, which did not respond to serotonin alone. The factor displayed no IFN or IL 2 activity as judged by the lack of antiviral activity and inability to support the growth of an IL 2-dependent cell line. In the presence of monocytes, serotonin (10(-5) M) was considerably more effective than human IFN-alpha or IFN-gamma at optimal concentrations and was about equally effective as IL 2 at a final concentration of 50 U/ml in a short-term NK assay. The potency and efficacy for serotonin were similar to that earlier reported for histamine in monocyte-containing effector cells. The NKCC-enhancing effect of serotonin was additive to that induced by IFN-alpha, IFN-gamma, or IL 2, but not to histamine. The presented data suggest an earlier unrecognized, serotonin receptor-mediated regulation of human NK cells.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Interferon and beta 2-microglobulin in patients with common variable immunodeficiency or selective IgA deficiency.

The production of interferon (IFN) after stimulation of peripheral blood mononuclear cells with Sendai virus or phytohemagglutinin was studied in patients with common variable immunodeficiency (CVID) or selective IgA deficiency. Cells from CVID patients produced significantly more Sendai virus-induced (alpha) and mitogen-induced (gamma) IFN than cells from healthy control subjects. By contrast, some patients with selective IgA deficiency produced subnormal amounts of IFN-alpha. Neither IFN-alpha nor IFN-gamma was detectable in sera from the two categories of patients using radioimmunoassays with sensitivity limits of 5-10 international units per milliliter. With the aid of a more sensitive bioimmunoassay, however, antiviral activity was detected more frequently in sera from patients with CVID than in sera from control individuals. Acid treatment and absorption with anti-IFN-alpha and anti-IFN-beta sera indicated that the antiviral activity was due to IFN, with no preponderance of any particular IFN type. Determination of beta-2-microglobulin (beta 2M) concentrations revealed that CVID patients had markedly, and IgA-deficient patients moderately increased serum levels of this substance, as compared to healthy blood donors. Since IFN enhances the synthesis of beta 2M the finding of increased levels of this substance in CVID would be consistent with the observed hyperproduction of IFN. The present findings are concordant with earlier observations of increased natural killer cell activity in at least some forms of CVID and suggest that increased activity of the IFN/natural killer cell system provides a mechanism which may compensate for the defective B cell function in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗