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Biomedical subjects

E Saksela

Publications and source records attributed to E Saksela.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cell proliferation correlates with prognosis in acinic cell carcinomas of salivary gland origin. Immunohistochemical study of 30 cases using the MIB 1 antibody in formalin-fixed paraffin sections.

Immunohistochemical staining with the MIB 1 antibody was used to assess cell proliferation in 30 cases of acinic cell carcinoma of salivary glands. Until now, no prognostic factors have been available for these rare tumours. The MIB 1 monoclonal antibody recognizes the Ki-67 antigen in formalin-fixed, paraffin-embedded tissues. A MIB 1 index was developed as a means of expressing the percentage of MIB 1-positive tumour cell nuclei, and the tumours were scored without prior information of clinical behaviour. The staining results were then compared with the clinical outcome of the patients. All eight patients who developed tumour recurrences had MIB 1 indices higher than 5 per cent. Tumour recurrences could be predicted even in cases of bland morphology and low mitotic rate. Three patients died of their recurrent tumours, and had MIB 1 indices of 56.2, 12.7, 7.8 per cent in their primary tumours. Five of seven patients with MIB 1 indices higher than 10 per cent had unfavourable outcomes. None of the 17 patients with MIB 1 indices lower than 5 per cent developed recurrences during follow-up periods up to 30 years. The present results indicate that MIB 1 staining appears to be a significant prognostic factor in acinic cell carcinomas of salivary gland origin.

Adolescent↗
PubMed1994

Human NK cells expressing alpha 4 beta 1/beta 7 adhere to VCAM-1 without preactivation.

The authors demonstrate that resting CD56+/CD3- NK cell adhesion to the endothelial VCAM-1 is over three-fold higher than CD56-/CD3+ T-cell adhesion. T-cell, but not NK-cell adhesion, to VCAM-1 is enhanced significantly by stimulation. The expression of VCAM-1 receptor subunits alpha 4 and beta 1 on both effector cells remains unchanged upon stimulation. A subpopulation of NK cells, as well as of T cells, was found to express beta 7, whose expression was not altered upon stimulation. The authors conclude that the adhesive properties of the same receptor structures on these distinct cell populations are regulated in a different manner, according to the specific functions of the effector cells of the immune system.

Antigens, Neoplasm↗
PubMed1993

Deacetylase activity of human tumor cells producing immunosuppressive aminosugars: its possible role in resistance to cell-mediated cytotoxicity.

In the present study, we examined the presence of deacetylases capable of producing free hexosamines, which we have shown earlier to be immunosuppressive against human natural killer (NK) cell-mediated cytotoxicity, from N-acetylhexosamines in human tumor cells. When human NK-resistant colon cancer cells (Colo-320DM) were incubated with acetyl-D-[1,6-3H(N)]glucosamine, a significant conversion to [3H]glucosamine occurred. Deacetylation was demonstrated as a change of the substrate radioactivity into free glucosamine trapped by a cation exchange resin, and this was subsequently confirmed by paper chromatography. This deacetylase activity was detected in other NK-resistant tumor cell lines, especially in freshly isolated human renal and breast cancer cells and testicular seminoma cells. However, no deacetylase activity was detected in NK-sensitive target cells such as K562, MOLT-4, or HL-60 cells. The ability to produce free hexosamines from N-acetylated aminosugars may provide a new mechanism for the escape of tumor cells from the attack of immune effector cells such as NK cells.

Acetylglucosamine↗
PubMed1993

A sub-set of immediate early mRNAs induced by tumor necrosis factor-alpha during cellular cytotoxic and non-cytotoxic responses.

TNF-alpha is a multifunctional cytokine which is cytotoxic for some cell lines. In order to characterize the early genomic response to TNF-alpha, we have analyzed the induction of a sub-set of serum-inducible immediate early genes in WEHI-S and L929 fibrosarcoma cell lines, which are sensitive to TNF-alpha, and in the 3T3-LI pre-adipocytic cell line, which is resistant to TNF-alpha cytotoxicity. Among 77 immediate early mRNAs screened by dot blot and/or Northern blot analyses, the expression of 23 mRNAs was found to be induced by TNF-alpha. Ten of these mRNAs encode proteins known to function as pro-inflammatory cytokines or transcription factors, while 13 others have as yet uncharacterized activities. The magnitude of c-fos induction by TNF-alpha inversely correlated with cell-type-specific cytotoxicity. Rapid and transient mRNA responses were observed in the TNF-alpha-resistant cells, whereas a slower and more persistent response was characteristic for TNF-alpha-sensitive cells. The prolonged induction of immediate early mRNAs may contribute to TNF-alpha-induced cellular cytotoxic responses.

Animals↗
PubMed1993

Tumor necrosis factor-alpha and interferon-gamma inhibit insulin-like growth factor II gene expression in human fetal adrenal cell cultures.

Insulin-like growth factor-II (IGF-II) gene expression is induced by adrenocorticotropic hormone (ACTH) in human fetal adrenals (HFA), which suggests an important role for IGF-II in HFA growth and differentiation. Many cytokines have different regulatory actions in the endocrine glands. In the present study we have investigated the effects of two cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), on the regulation of IGF-II gene expression in cultured HFA cells. Both TNF-alpha and IFN-gamma inhibited basal and ACTH-induced accumulation of IGF-II mRNA dose-dependently. Cell viability was not altered by treatment with TNF-alpha or IFN-gamma. In addition, the combination of TNF-alpha and IFN-gamma decreased ACTH-induced IGF-II mRNAs more potently than each cytokine alone. Our results suggest that TNF-alpha and IFN-gamma may be involved in the regulation of HFA growth and differentiation via local IGF-II production.

Adrenal Glands↗
PubMed1993

Prognostic markers in epithelial ovarian cancer.

Useful prognostic markers are available in certain areas of clinical management of epithelial ovarian tumors. CA125 and the flow cytometric determinants of DNA index and S-phase fraction are of obvious value in evaluating the outlook of patients particularly in stage II and more advanced cases as well as in the follow-up for recurrent disease. Combinations of other serological markers with CA125 add to the usefulness and may increase the proportion of stage I cases scoring positive with these tests. At the moment, none of the molecular biological markers associated with the oncogen and growth-suppressor gene derangement pathways can be used as candidates for screening markers. Development in this area is very rapid, however, and with increasing understanding of such key conceptual questions as the biological nature of the ovarian borderline tumors, more accurate prognostic markers will emerge.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1993

Contact of lymphocytes with Helicobacter pylori augments natural killer cell activity and induces production of gamma interferon.

We studied the capacity of glutaraldehyde-fixed Helicobacter pylori to stimulate natural killer (NK) cell activity. Bacteria were incubated overnight with peripheral blood lymphocytes enriched for large granular lymphocytes (LGL), the mediators of non-major histocompatibility complex-restricted cellular cytotoxicity. Then, the cytolytic activity of LGL was tested against various tumor target cells. We observed that efficient cytolytic activity was generated against resistant and nonresistant tumor target cell lines. Nine local clinical isolates of H. pylori and the reference strain NCTC 11637 were tested, and they all were equally effective in inducing NK cell activity. However, flagellin antigen, glycine extract, urease, and lipopolysaccharide prepared from H. pylori NCTC 11637 all failed to induce significant NK cell activity. The supernatants which were collected after coincubation of bacteria with LGL contained a factor(s) which could activate resting LGL into efficient cytolytic activity. The supernatants were also analyzed for interferon (IFN) activity. We observed that high titers of IFN were produced and that IFN activity was neutralized with anti-gamma interferon (IFN-gamma) antiserum, but not with anti-IFN-alpha antiserum. Thus, contact of lymphocytes with H. pylori leads to efficient stimulation of NK cell activity and the production of IFN-gamma.

Cells, Cultured↗
PubMed1992

The presence of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells: their possible role in swainsonine-augmented human NK cytotoxicity.

In the present study we examined the expression of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells and investigated their possible role in the human NK-cell phenomenon. The incubation of either peripheral-blood lymphocytes (PBL) or large granular lymphocytes (LGL) with swainsonine (SW), an inhibitor of mannosidase II, resulted in the augmentation of cytotoxicity against K562 leukemia cells. The enhanced cytotoxicity was associated with increased binding of fluorescein isothiocyanate-conjugated Con-A to SW-treated effector cells, and immunofluorescence staining of the target K562 cells using goat anti-Con-A antibody (Ab) showed a significant positive shift in the flow cytometric pattern. Electrophoretic separation and immunoblotting analysis revealed that 4 components with a molecular weight of approximately 95, 80, 60 and 50 kDa were recognized by anti-Con-A Ab from the detergent-extract of K562 cells. The addition of Con-A during the antibody incubation step of the Western blotting abolished their expression, thus excluding non-specific binding of the antibody. The addition of Con-A also strongly inhibited the cytotoxicity of SW-treated effector cells (PBL or LGL) against K562 cells, and this inhibition was abolished by 40 mM alpha-methyl-mannopyranoside (alpha-MM), which binds to Con-A. Furthermore, Con-A increased the binding frequency of SW-treated LGL to K562, in spite of the inhibited cytotoxicity, and this effect could be neutralized by the further addition of alpha-MM. Our results suggest that Con A-like molecules might play an important role in cell-cell interactions between SW-treated effector cells and NK target cells.

Adenosine Triphosphate↗
PubMed1992

Involvement of beta 2-integrins in the migration of human natural killer cells.

Human large granular lymphocytes with the NK cell phenotype (CD16+ or CD56+CD3-) were greatly enriched among the cells which migrated spontaneously through untreated or albumin-coated, 3-microns pore size polycarbonate filters for 1 to 8 h. Three days of rIL-2 treatment (300 IU/ml) and 3 to 5 wk of rIL-2 treatment (100 IU/ml) generated a 2.7 +/- 0.9-fold and 5.6 +/- 0.8-fold increase in cell migration, respectively. The adhesion and subsequent migration of freshly isolated NK cells was mainly mediated by CD11b/CD18, because migration could be inhibited by 80 +/- 8% anti-CD11b (Mac-1) antibodies but not with antibodies against CD11a (LFA-1) or CD11c (p150,95), the other alpha-chains of the beta 2-integrins. After rIL-2 activation, however, CD11a/CD18 was the major receptor utilized in migration, inasmuch as anti-CD11a antibody caused a 69 +/- 8% reduction in the number of migrated cells. Anti-CD11b antibody decreased migration by 43 +/- 12%, and together these antibodies inhibited migration by 82 +/- 7%. Anti-CD11a alone did not have any effect on adhesion, but CD11a/CD18 cooperated in the adhesion because anti-CD11b decreased adhesion by 40 +/- 11% and together these antibodies inhibited adhesion by 74 +/- 6%. The ability of large granular lymphocytes to rapidly utilize beta 2-integrins and unidentified ubiquitous ligands for binding and migration may be significant for their capacity to function in the first line of immune defense under highly variable conditions.

Antibodies, Monoclonal↗
PubMed1992

Analysis of collagen isotypes in crystalloid structures of salivary gland tumors.

Extracellular collagenous crystalloids (CCs) have been reported in salivary gland tumors. To study the occurrence and characteristics of these structures we reviewed 230 pleomorphic adenomas and myoepitheliomas of both major and minor salivary glands. Twelve of these cases contained crystalloids composed of radially arranged collagen fibers. However, no CCs were found in 124 malignant salivary gland tumors of different types. We show that CCs contain types I and III collagen but not type II, IV, or VI collagen. Moreover, cells surrounding CCs expressed the basement membrane molecules laminin and type IV collagen. These cells also showed other immunohistochemical features typical of myoepithelial cells.

Adenoma, Pleomorphic↗
PubMed1992

Adhesion molecules involved in the interaction of LGL/NK cells and human endothelial cells stimulated with Salmonella bacteria.

Previously we showed that pretreatment of LGL/NK or HUVE cells with Salmonella bacteria augments the adhesion of LGL/NK cells to endothelium. Here we analyse the roles of HUVEC adhesion molecules VCAM-1, ICAM-1 and E-selectin, and the counter-receptors VLA-4, LFA-1 and SLex in the increase of LGL/NK adhesion to HUVEC, stimulated with Salmonella Minnesota mR595 bacteria, LPS or TNF-alpha. On Salmonella-stimulated HUVEC, VCAM-1 and ICAM-1 were the major binding structures involved, and their effect was additive in monoclonal antibody inhibition experiments. We could demonstrate the induction of both structures on cultured HUVEC after 24 h of Salmonella stimulation in flow cytometric analysis. For Salmonella-stimulated LGL/NK, the principal binding structure was LFA-1. Stimulation of LGL/NK cells did not alter the expression of the adhesion structures (subunits CD11a/CD18, CD49d/CD29), as determined by flow cytometric analysis, and thus the increased adherence is presumably produced by an increased avidity of the receptors on LGL/NK cells. Pretreatment of endothelium or lymphocytes with various stimuli, including Salmonella bacteria or LPS, leads to an activation state which provides for characteristic anchorage sites for the increased migration of LGL/NK cells towards the site of inflammation.

Antibodies, Monoclonal↗
PubMed1991

Fibronectin facilitates the migration of human natural killer cells.

The interaction of lymphocytes with the extracellular matrix plays an important role in the immune defence against tumor cells and virus-infected cells. We have examined the effect of matrix proteins on the migration of large granular lymphocytes (LGL) through 3-microns pores in Nuclepore filters in a Boyden invasion chamber. Fibronectin bound on the filter surface significantly increased (p less than 0.001) the capacity of LGL to migrate, whereas soluble fibronectin did not. In addition, a significantly higher (p less than 0.001) percentage of LGL was capable of migration through fibronectin-coated filters than through untreated filters. With fibronectin-coated filters, a strong enrichment of CD16+ and CD56+CD3- cells with LGL morphology and reduction of CD3+ cells was found among migrating cells when the incubation time was 4 h or less. Later agranular lymphocytes, mainly CD3+ T lymphocytes, also started to migrate. Laminin coating of filters also facilitated migration, and when filters were coated with both fibronectin and laminin the increase in migration was equal to the sum of the increases induced by each protein alone. Interactions between cell surface and the Arg-Gly-Asp (RGD) peptide sequence of many matrix proteins had no role in the LGL migration through untreated filters. However, when filters were coated with either fibronectin or laminin, or with both, peptide containing the RGD sequence reduced migration to the level of untreated filters, whereas an Arg-Gly-Glu control peptide had no effect. Our results show that unstimulated LGL/natural killer cells are capable of rapid migration through matrix-coated porous membranes, and that interactions between cell surface receptors and the RGD sequence of fibronectin and probably laminin are utilized in this process.

Antigens, CD↗
PubMed1991

Myxoma of the external auditory meatus.

A case of myxoma of the external auditory meatus is described. The patient presented with a recurring tumour which had not been correctly diagnosed although the growth had been removed ten times over a period of two years. The tumour was skin covered, contained gelatinous material and was attached to the tympanic membrane and anterior canal wall. Following recognition of the tumour as myxoma, removal was performed with sufficiently wide margins and there has been no recurrence during follow-up for one year.

Adult↗
PubMed1991

Human natural killer cells express different integrins and spread on fibronectin.

Human natural killer (NK) cells adhered and most of them also actively spread on cellular fibronectin (cFn), plasma Fn (pFn) and its Mr 120,000-140,000 or Mr 105,000 cell-binding proteolytic Fn-fragments as well as on heparin-binding Fn-fragments containing the alternative cell binding site. The cells did not spread on vitronectin, laminin or collagens. Adhesion on Mr 105,000 Fn fragment containing the cell binding site, could be prevented by the synthetic peptide GRGDS but not by an inactive peptide, whereas adhesion on heparin-binding Fn fragments was unaffected by the peptide. Spreading of the NK cells led to a distinct reorganization of F-actin. Immunoprecipitation with monoclonal antibodies (MoAb) against the beta 1 integrin subunit of radioactively surface-labelled cells revealed a broad polypeptide band of Mr 140,000 under reducing conditions and a polypeptide doublet of Mr 160,000 and Mr 110,000 under non-reducing conditions. Identical polypeptides, corresponding to the alpha- and beta-subunits of the Fn-receptor complex, were bound to the Mr 105,000 chymotryptic Fn-fragment coupled to Sepharose. Similar experiments with small lymphocytes did not reveal any polypeptides. Immunofluorescence results with McAbs suggested that among the alpha-subunits of integrins, the alpha 3, alpha 4, and alpha 5 subunits are expressed in NK cells. The present results suggest that non-activated NK cells, but not small lymphocytes, express beta 1-integrins, and that at least the Fn-receptors alpha 4 beta 1 and alpha 5 beta 1 may function in the adhesion and migration of NK cells.

Cell Adhesion↗
PubMed1991

Effect of Salmonella bacteria on the interaction of human NK cells with endothelial cells.

Leukocyte-endothelial cell adhesion and its regulation are essential and complex initial aspects of lymphocyte migration. Various factors (IL-1, TNF-alpha, IFN-gamma etc.) have been shown to increase the endothelial adhesiveness for human lymphocytes, including natural killer cells (NK cells). In this work we have demonstrated that pretreatment of either the target endothelial cell monolayers or the binding LGL-cells with mR595 Salmonella Minnesota bacteria results in a substantial increase in the adhesiveness of LGL-cells to endothelial cells. The increase was more prominent when the endothelial cells were treated than when the adhering LGL-cells were similarly pretreated. The adhering cell population was significantly enriched with CD56 (Leu19) and CD16 positive cells, i.e. cells with NK cell phenotype, when the lymphocyte population was pretreated. However, the pretreatment of EC resulted in a non-specific increase in EC adhesiveness since the relative proportion of CD56+ (Leu19), CD16+ and CD3+ cells among the adhering cells did not significantly differ from the starting population. The bidirectional enhancement of adhesiveness of human NK cells to endothelium by mR595 Salmonella bacteria may be significant in the host defense responses against microbial infections.

Antigens, Differentiation↗
PubMed1991

Potentiation of human natural killer cell cytotoxicity by Salmonella bacteria is an interferon- and interleukin-2-independent process that utilizes CD2 and CD18 structures in the effector phase.

Incubation of large granular lymphocytes (LGL) with glutaraldehyde-fixed bacteria stimulated in the supernatant the production of interferon (IFN), which proved to be mainly IFN-gamma. Even though IFN-gamma was produced upon exposure of LGL to bacteria, anti-IFN-gamma antibodies failed to interfere with induction of cytotoxicity by bacterial contact. Anti-IFN-gamma receptor antibodies had no effect on the induction of activated killing by bacterial contact either. We also tested the effect of anti-IFN-alpha antibody, but it failed to interfere with induction of cytotoxicity by bacterial contact. No interleukin-2 (IL-2) was detected in the culture supernatant of bacterially activated LGL by the mouse HT2 cell assay, nor did we detect any IL-2 mRNA in bacterially activated LGL by Northern RNA blot assay. Neutralizing anti-IL-2 antiserum had no effect on the induction of activated killing by bacterial contact, and recombinant IL-4 did not interfere with the induction of activated killing. We then studied the membrane structures involved in bacterially activated killing. Anti-CD18 monoclonal antibody did not interfere with the induction phase of bacterially activated killing. However, both anti-CD18 and anti-CD2 antibodies inhibited the effector phase of bacterially activated killing. The effector pathways utilized by activated LGL depended on the mode of activation in that even though bacterially activated LGL were sometimes blocked by anti-CD2 monoclonal antibody, recombinant-IL-2-stimulated LGL were not. In conclusion, our present results suggest that there may be mediators other than exogenously secreted IFNs and IL-2 which are responsible for the induction of activated killing after bacterial contact. CD18 and CD2 structures were shown to be involved in the effector phase of bacterially activated killing.

Antibodies, Monoclonal↗