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T Timonen

Publications and source records attributed to T Timonen.

At least 19 recordsLinked to original sources
PubMed2000

Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Inhibition of human NK cell function by valinomycin, a toxin from Streptomyces griseus in indoor air.

Streptomyces griseus strains isolated from indoor dust have been shown to synthesize valinomycin. In this report, we show that human peripheral blood lymphocytes treated with small doses (30 ng ml(-1)) of pure valinomycin or high-pressure liquid chromatography-pure valinomycin from S. griseus quickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml(-1)) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml(-1) dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte-macrophage colony-stimulating factor and gamma interferon (IFN-gamma) production by NK cells. However, IFN-gamma production induced by a combination of IL-15 and IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect of the cytokine combination against valinomycin. Thus, valinomycin in very small doses may profoundly alter the immune response by reducing NK cell cytotoxicity and cytokine production.

Air Microbiology↗
PubMed1999

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors.

The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein EIB19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.

Actins↗
PubMed1998

Comparison between four and eight cycles of intensive chemotherapy in adult acute myeloid leukemia: a randomized trial of the Finnish Leukemia Group.

In acute myelogenous leukemia (AML) intensive postremission treatment is needed for an optimal result. However, it is not known how long the treatment should last and how many courses are necessary. The object of this prospective study was to compare four and eight intensive chemotherapy cycles in the treatment of adult de novo AML. In a multicenter study, 248 consecutive patients, aged from 16 to 65 years, were treated with intensive induction treatment. The patients in remission after two courses were randomized to receive either two (short arm) or six (long arm) additional intensive cycles of chemotherapy. The median follow-up time of the living patients is 68 months. Of the patients, 77% achieved complete remission, and 36% of all patients survived for 5 years. Seventy-three patients were randomized to the short arm and 66 to the long arm. There was no significant difference in the relapse-free survival (median 21 months vs 17 months) or overall survival (43 months vs 39 months) between the short and long arms, respectively. Treatment-related deaths occurred in 31 patients (13%), 11 of them in first remission. More than one-third of the patients survived for 5 years. It seems probable that the first few months after diagnosis are decisive for the prognosis if the chemotherapy is intensive, and further treatment cannot markedly influence the outcome.

Aclarubicin↗
PubMed1998

Successful treatment of platelet transfusion refractoriness: the use of platelet transfusions matched for both human leucocyte antigens (HLA) and human platelet alloantigens (HPA) in alloimmunized patients with leukaemia.

Six patients, 4 with acute myeloid leukaemia and 2 with a myelodysplastic syndrome who were refractory to random donor platelet transfusions and alloimmunized to human leucocyte antigens (HLA) and human platelet alloantigens (HPA), were treated with HLA- and HPA-matched platelet transfusions. In all the patients refractoriness and alloantibodies to HLA as well as HPA-1b or HPA-5b were detected simultaneously. Sixty-seven transfusions (445 units) of HLA- and HPA-matched platelets were given and responses to them were, in general, satisfactory in all the patients. No major spontaneous bleeding occurred. Four patients underwent bone marrow transplantation despite alloimmunization. The percentages of platelet transfusion days with a platelet nadir below 20x10(9)/l were 88% for the last 3 random donor platelet transfusions and 39% for the first 3 HLA- and HPA-matched platelet transfusions, respectively (p=0.009, Fisher's exact test). Four patients received also HLA-matched platelets, but responses to them were poor. The small number of transfusions with HLA-matched platelets precluded comparisons to either the random donor or HLA- and HPA-matched platelet transfusions. It seems that HLA- and HPA-alloimmunized patients can be successfully supported with HLA- and HPA-matched platelet concentrates.

Adult↗
PubMed1998

Long-term supplementation with alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers.

OBJECTIVE: To assess the effect of alpha-tocopherol and beta-carotene supplementation on the prevalence of oral mucosal lesions in smokers. DESIGN: An end-point examination of a random sample of participants in a controlled trial for 5-7 years (Alpha-Tocopherol Beta-Carotene Cancer Prevention Study) in Helsinki, Finland. SUBJECTS: A total of 409 white male cigarette smokers, aged 55-74 years who received either alpha-tocopherol (50 mg per day) or beta-carotene (20 mg per day) supplementation, both of these or placebo capsules. METHODS: Clinical examination of oral mucosae, histological examination of lesions showing leukoplakia and cytological examination of buccal epithelium. Statistical analysis using Fisher's exact test. RESULTS: No statistically significant differences were found between the study groups either in the prevalence of oral mucosal lesions or in the cells of unkeratinized epithelium. Leukoplakia was present in 24 (5.9%) of the subjects. Seven lesions showed dysplasia. CONCLUSION: The present study on oral health does not support the hypothesis that alpha-tocopherol or beta-carotene supplementation plays an essential role in preventing oral mucosal changes in smokers.

Aged↗
PubMed1997

Natural killer cells: endothelial interactions, migration, and target cell recognition.

Natural killer (NK) cells form a unique third group of lymphocytes that differs from T and B cells in surface phenotype, target recognition, and function. By producing cytokines and exerting cytotoxicity, NK cells participate in the resistance against microbial infections and malignant disease. The research on the molecular mechanisms of migration and target cell recognition by NK cells has recently developed rapidly. NK cells express a number of adhesion molecules common to hematopoietic lineage, bind to endothelium, extravasate, and respond to chemotactic stimuli, much resembling T cells in those respects. However, NK cells are probably capable of transmigration and infiltration merely through activation by cytokines and chemokines, as opposed to the requirement of antigen presentation in the initial activation of T cells. Target cell recognition and ensuing cytotoxicity of NK cells is a sum effect of a delicate balance between the effects of inhibitory and activating NK cell receptors. NK cells express several well-defined MHC I-recognizing receptors that inactivate their functions. In pathological alterations of MHC I expression, the inhibitory receptors do not engage and thus permit the lysis of the target cell. The receptors that trigger the cytolytic machinery of NK cells are less well known. Some candidate triggering receptors have been identified and it seems that NK cell triggering is mediated by multiple receptors, as is the inhibition of cytotoxicity. For example, NK cells clearly detect target cell-bound antibodies and thus mediate antibody-dependent cytotoxicity. They may also detect carbohydrate moieties, normal but pathologically distributed adhesion molecules, as well as ligands for a number of co-stimulatory receptors.

Animals↗
PubMed1997

Lymphocyte adhesion molecule ligands and extracellular matrix proteins in gliomas and normal brain: expression of VCAM-1 in gliomas.

To identify antigenic differences between gliomas and normal brain, we have immunohistochemically studied the expression of lymphocyte adhesion molecules (ICAM-1, ICAM-2, ICAM-3, VCAM-1, E-selectin and CD58), epidermal growth factor receptor (EGFR) and extracellular matrix proteins (collagen IV, fibronectin, laminin, merosin, tenascin and vitronectin) in these tissues. Gliomas expressed high levels of ICAM-1, CD58 (LFA-3), EGFR, tenascin and vitronectin, whereas only very low levels were detected in normal brain. VCAM-1 expression was detected in 15 out of 25 gliomas but not in normal brain. The presence of VCAM-1 in gliomas was verified by immunoblotting and RNase protection assay, and in glioma cell lines by Northern blotting. Expression of VCAM-1 in gliomas may partially explain lymphocytic infiltration, and anti-VCAM-1 antibodies may be of potential in antibody mixtures for targeted therapy of gliomas.

Adult↗
PubMed1997

Intensive chemotherapy of poor prognosis myelodysplastic syndromes (MDS) and acute myeloid leukemia following MDS with idarubicin and cytarabine.

Forty patients with high risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) preceded by MDS were treated with intensive induction and consolidation chemotherapy in a prospective multicenter pilot study. They were given two cycles of cytarabine 100 mg/m with 12-h intervals on days 1-7 and idarubicin 12 mg/m2 on days 5-7, both intravenously. Patients who were in remission after these two cycles were given two further cycles of cytarabine on days 1-5 and idarubicin on day 5. No maintenance treatment was given. Eleven out of 19 MDS patients (58%) and 10 out of 21 AML patients (48%), in total 21 out of 40 patients (53%), entered remission. Eight patients underwent allogeneic bone marrow transplantation. The follow-up time was 13-48 (median 33) months. At the time of the analysis, seven patients survived, four patients with MDS all of whom had been treated with bone marrow transplantation (three in continuous remission), and three patients with AML treated with chemotherapy only (two in continuous remission). The median survival of the patients treated with chemotherapy only was 12 months, with the median progression-free survival being 8 months. In view of the poor prognostic factors of the patients, the remission rate was satisfactory, but the responses as well as the survival were short. The post-remission treatment needs to be improved.

Adult↗
PubMed1997

The ezrin protein family: membrane-cytoskeleton interactions and disease associations.

Ezrin, radixin, moesin and merlin form a subfamily of conserved proteins in the band 4.1 superfamily. Ezrin protein subfamily members act as linkers between the plasma membrane and the cytoskeleton. Members of the subfamily have been shown to interact with each other, with cell adhesion molecules such as CD44 and with F-actin. Recent data indicate that intercellular adhesion molecules 1 and 2 also interact with ezrin. The proteins are also involved in the redistribution of intercellular adhesion molecules and the organization of cell membrane structures. Merlin is a tumor suppressor that is involved in tumorigenesis of schwannomas and meningiomas. Merlin has the same overall protein structure as the other proteins in the subfamily but may have partially distinct functions.

Animals↗
PubMed1997

Natural killer cell-target cell interactions.

Research into the molecular mechanisms of target cell recognition by natural killer (NK) cells has recently progressed rapidly. NK cells express several MHC I recognizing receptors that inactivate the NK cells' functions. In pathological alterations of MHC I expression, the NK cell inhibitory receptors do not engage and thus permit the lysis of the target cell. The receptors that trigger the cytolytic machinery of NK cells, after the permission of lysis from the inhibitory receptors, are poorly characterized. Some candidate triggering receptors have been identified and it seems that triggering of NK cell killing is mediated by multiple receptors, as is the inhibition of cytotoxicity.

Animals↗
PubMed1996

ICAM-2 redistributed by ezrin as a target for killer cells.

Very little is known about the receptors and target molecules involved in natural killer (NK) cell activity. Here we present a model system in which interleukin-2-activated killing by NK cells depends on the intercellular adhesion molecule ICAM-2 and is regulated by the distribution of ICAM-2. The level of ICAM-2 expression in NK-sensitive and resistant cells is similar, but in sensitive cells ICAM-2 is concentrated into bud-like cellular projections known as uropods, whereas in resistant cells it is evenly distributed. The cytoskeletal-membrane linker protein ezrin is also localized in uropods. Transfection of human ezrin into NK-resistant cells induces uropods formation, redistribution of ICAM-2 and ezrin, and sensitizes target cells to interleukin-2-activated killing. These results reveal a new mechanism of target-cell recognition: cytotoxic cells recognize adhesion molecules that are already present on normal cells, but in diseased cells are concentrated into a biologically active cell-surface region by cytoskeletal reorganization. The results also highlight the importance of cytoskeletal interactions in the regulation of ICAM-2-mediated adhesive phenomena.

Animals↗
PubMed1996

Different expression of adhesion molecules on stromal cells and endothelial cells of capillary hemangioblastoma.

Cell-cell and cell-matrix interactions are essential for many basic functions, including differentiation and development. In pathological conditions such as inflammation and tumorigenesis adhesive events also play a major role. Cellular adhesion is mediated by specific molecules expressed by both normal and neoplastic tissues. Capillary hemangioblastoma is a tumor of controversial origin, characterized by two major components, vacuolated stromal cells and a capillary network. In order to shed light on the differentiation of the stromal cells and the interactions between the two major components of hemangioblastoma we studied the expression of several adhesion molecules by immunocytochemistry. The endothelium-associated adhesion molecules (ICAM-1, ICAM-2, VCAM-1, PECAM-1 and ELAM-1) were expressed by endothelial cells within the tumors, but not by stromal cells. In contrast, the stromal cells showed strong neuronal cell adhesion molecule (NCAM/CD56) expression, further distinguishing them from endothelial cells. In addition, the stromal cells expressed CD44, which is of interest, as this membrane protein is linked to ezrin, a cytoskeleton-associated protein also expressed by stromal cells. We conclude that the stromal cells and endothelial cells of capillary hemangioblastoma exhibit quite divergent expression patterns of adhesion molecules. The NCAM expression in stromal cells suggests neuroectodermal or mesenchymal differentiation of this tumor. In addition, the NCAM expression could contribute to the sometimes problematic differential diagnosis between capillary hemangioblastoma and metastatic renal cell carcinoma of the central nervous system.

Capillaries↗
PubMed1996

Expression of complement membrane regulators membrane cofactor protein (CD46), decay accelerating factor (CD55), and protectin (CD59) in human malignant gliomas.

Gliomas are malignant brain tumors, which, despite recent progress in surgical and radiological treatment, still have a poor prognosis. Since gliomas apparently resist immunological clearance mechanisms, we became interested in examining bow gliomas resist killing by the human complement system. The resistance of human cells to complement-mediated damage is, in large part, mediated by specific inhibitors of complement:membrane cofactor protein (CD46), decay-accelerating factor (CD55), and protectin (CD59). In the present study we examined the expression of complement regulators in 14 human glioma tumors and in 7 glioma cell lines (U251, U87, HS683, U373, U138, U118, and H2). Protectin was found to be strongly expressed by all glioma tumors and cell lines. Northern blotting analysis demonstrated the typical pattern of four to five protectin mRNAs in the glioma cells. Except for blood vessels, the expression of decay-accelerating factor was weak or absent in the tumors in situ, whereas in the cell lines its expression varied, ranging from negative to intermediate. Membrane cofactor protein was moderately expressed by all the cell lines but only weakly in the tumors. Cell-killing experiments demonstrated that the glioma cell lines were exceptionally resistant to C-mediated lysis. Five of the seven cell lines (U373, HS683, U118, U138, and H2) resisted complement lysis under conditions where most other cell lines were sensitive to killing. Neutralization experiments using specific monoclonal antibodies indicated that protectin was functionally the most important complement regulator in the glioma cells. The killing of the U87 and U251 cells could be significantly increased by a blocking anti-protectin monoclonal antibody, whereas for the other cell lines only moderate or no response was observed. The H2 cell line resisted killing by all antibodies and by complement. These results show that protectin is the most important complement regulator on human glioma cells. The exceptional complement resistance of some glioma cell lines suggests that they may utilize other, hitherto less well characterized, mechanisms to resist complement killing.

Adult↗
PubMed1995

Activation of natural killer cell migration by leukocyte integrin-binding peptide from intracellular adhesion molecule-2 (ICAM-2).

Intracellular adhesion molecule-2 (ICAM-2), one of the ligands of CD11a/CD18 (LFA-1), is mainly expressed on endothelial and hematopoietic cells. The biological significance of ICAM-2 has remained unclear. Previous findings have shown that a peptide from ICAM-2, spanning residues 21-42 from the first immunoglobulin domain, enhances natural killer (NK) cell cytotoxicity and induces T cell aggregation. We have now studied the effect of the same ICAM-2 peptide on NK cell migration in the Boyden chamber assay. The peptide significantly increased NK cell migration up to 215 +/- 21%, as compared to migration of control cells (100%), and the induction was inhibited by anti-CD11a monoclonal antibodies. The ICAM-2 peptide also induced polymerization of F-actin at the leading edge of migratory NK cells. Cross-linking of CD11a/CD18 receptors with anti-CD11a or anti-CD18 monoclonal antibodies and secondary antibodies resulted in receptor recycling, increased migration, and actin polymerization, but led to slight inhibition of cytotoxicity. The ICAM-2 peptide did not induce such a receptor recycling. Phosphotyrosine immunoblotting experiments showed that the ICAM-2 peptide increased the phosphorylation of 150- and 35-kDa proteins. During cross-linking with antibodies, only the 150-kDa protein showed increased phosphorylation. The results show that depending on the type of CD11a/CD18 receptor ligation different kinds of signals are transduced in NK cells. These signals may either trigger only locomotion, or both locomotion and cytotoxicity. Based on these findings, a major function for ICAM-2 on endothelium may be triggering of migration of adhering leukocytes.

Actins↗