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O Lassila

Publications and source records attributed to O Lassila.

At least 19 recordsLinked to original sources
PubMed2001

Both normal and leukemic B lymphocytes express multiple isoforms of the human Aiolos gene.

Aiolos is a chromatin remodeling transcription regulator that plays an antiproliferative role in B lymphocyte function. In contrast to the related Ikaros factors, mammalian Aiolos has not been reported to generate splice variants. In addition, although human leukemic lymphoblasts express non-DNA-binding Ikaros isoforms with potential dominant negative effect on other interacting factors,the role of Aiolos in human lymphoid disorders has remained obscure. To address the question, why Aiolos should delineate from Ikaros in such a marked way, we have here analyzed whether also human Aiolos could generate alternate isoforms. According to the results obtained, both normal and neoplastic B lineage cells were found to express at least five novel Aiolos variants. Also structurally dominant negative variants with less than three DNA-binding domains were identified. In conclusion, given the multiplicity of also human Aiolos isoforms and thereby the evidently more intricate contribution of Aiolos to the chromatin remodeling machinery, it is suggested, that not only Ikaros, but also Aiolos could participate in a more versatile manner in the regulation of B lymphocyte function.

Alternative Splicing↗
PubMed2001

Cytokine levels in midtrimester amniotic fluid in normal pregnancy and in the prediction of pre-eclampsia.

Midtrimester amniotic fluid cytokines may reflect the function of the maternal immune system in the maternal-fetal interface and thus be predictive of pre-eclampsia. We determined the concentrations of interleukin (IL)-6, IL-8, IL-10, IL-11, IL-12, IL-15, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta in amniotic fluid at 14-16 weeks of gestation from women with normal pregnancies and from those who subsequently developed severe pre-eclampsia. The concentrations of the cytokines in amniotic fluid did not significantly differ between patients and normal controls. The median concentration of IL-6 was 950 pg/ml in normal pregnant women and 578 pg/ml in the patient group. The median concentration of IL-8 was 606 pg/ml in normal controls and 294 pg/ml in the patient group. The levels of IL-6, IL-8 and TGF-beta correlated positively with each other. TNF-alpha concentrations were low and similar in both groups. IL-10 and IL-12 were detected at very low levels in 37 and 7% of the samples, respectively. No difference was found in IL-15 concentrations between the groups. IL-11 was found only at low levels in both groups. Although none of the cytokines measured was predictive of pre-eclampsia, this study provides information of cytokines in amniotic fluid during the period when the spiral arteries are remodelled.

Adult↗
PubMed2001

Non-steroidal anti-oestrogens inhibit the differentiation of synovial macrophages into dendritic cells.

BACKGROUND: Dendritic cells (DC) have been suggested to play an important role in the pathogenesis of rheumatoid arthritis (RA). Agents that inhibit DC differentiation and function may have a therapeutic value in the treatment of RA. OBJECTIVE: To examine the effect of the non-steroidal anti-oestrogens toremifene and tamoxifen on the differentiation of synovial fluid (SF) macrophages into DC. METHODS: SF macrophages from patients with RA were cultured with interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF) in the presence or absence of anti-oestrogens. The expression of cell surface markers on SF antigen-presenting cells (APC) was studied by flow cytometry. The capacity of SF APC to stimulate allogeneic T cells was studied using the mixed lymphocyte reaction. The production of tumour necrosis factor-alpha, IL-10 and transforming growth factor-beta1 was studied using ELISA. RESULTS: Anti-oestrogens inhibited the differentiation of SF macrophages into DC and the capacity of SF macrophage-derived DC to stimulate allogeneic T cells. CONCLUSIONS: By inhibiting the differentiation of SF macrophages into DC, non-steroidal anti-oestrogens may have beneficial effects in RA.

Aged↗
PubMed2000

Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells.

Dendritic cells (DC) are professional antigen-presenting cells with a unique capacity to initiate and regulate immune responses. Immature CD1a(+) DC can be cultured from CD14(+) monocytes in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in vitro. Results of this study show that the nonsteroidal anti-estrogens toremifene and tamoxifen inhibit this differentiation. In the presence of anti-estrogens the cells lose CD14 expression, but remain CD1a(-) and clearly have less dendritic processes than immature DC. Functionally, anti-estrogen-treated cells are inferior to immature DC in inducing proliferation of allogeneic T cells and in producing IL-12 p70 protein after CD40 ligation. The expression of the costimulatory molecules CD80 and CD86 is differentially regulated by anti-estrogens during DC differentiation. Furthermore, anti-estrogens are also able to inhibit the terminal maturation of DC. By inhibiting the functional differentiation of DC, anti-estrogens may have a role in the treatment and prevention of autoimmune diseases. (Blood. 2000;95:2875-2882)

Antigens, CD↗
PubMed2000

Interleukin-15 up-regulates the expression of CD154 on synovial fluid T cells.

To investigate the role of the CD40-CD154 interaction in rheumatoid arthritis (RA), we analysed the expression of CD154 on CD3+ and CD4+ T cells in synovial fluid (SF) from patients with RA and in peripheral blood (PB) from patients and normal controls. As interleukin (IL)-15 is a potent activator of synovial T cells we wanted to study whether IL-15 also regulated the expression of CD154 on these T cells. Freshly isolated synovial T cells did not express significant levels of CD154, as evaluated using flow cytometry, whereas the expression of CD86 and human leucocyte antigen (HLA)-DR was significantly elevated on SF T cells when compared with PB T cells from patients or controls. Synovial T cells could up-regulate their CD154 expression following activation with phorbol 12-myristate 13-acetate (PMA) + ionomycin or anti-CD3 + anti-CD28 monoclonal antibodies (mAbs), but the maximal level of expression remained lower than in control T cells. IL-15 significantly increased the expression of CD154 on SF and PB T cells from patients, whereas IL-2 had minimal effects. Furthermore, IL-15 induced extensive proliferation in SF T cells. Our results show that SF T cells up-regulate the expression of CD154 in the presence of IL-15, a cytokine present in the synovium of patients with RA. These results further emphasize the role of IL-15 in the pathogenesis of RA.

Adult↗
PubMed2000

Toremifene increases the expression of intercellular adhesion molecule-1 (ICAM-1) on MCF-7 breast cancer cells and Jurkat cells.

The present study was conducted to reveal the effect of the nonsteroidal anti-oestrogen toremifene on the expression of cell-surface molecules involved in the immunogenicity of tumours or the sensitivity of tumour cells to apoptotic cell death. We studied the effect of toremifene on the expression of HLA-DR, ICAM-1, costimulatory molecules CD80 and CD86, and the tumour necrosis factor receptor (TNF-R) family molecules CD27, CD30, CD40, TNF-R1, TNF-R2 and Fas (CD95) on MCF-7 breast cancer and Jurkat T cells. In addition, the effect of toremifene on Fas-mediated apoptosis was studied. Toremifene did not affect Fas expression or Fas-mediated apoptosis in Fas-resistant MCF-7 or Fas-sensitive Jurkat cells, but was found to increase the expression of ICAM-1 in both cell lines. In addition, toremifene increased the expression of CD40 and CD80 on MCF-7 cells. The expression of ICAM-1 in tumours plays an important role in the interaction of tumour cells and effector cells of the immune system. Therefore, we suggest that toremifene may modulate the immunogenicity of tumour cells by increasing the expression of ICAM-1.

Antineoplastic Agents, Hormonal↗
PubMed2000

Prethymic progenitors from the avian para-aortic mesoderm express GATA-3 and distinct chTcf isoforms but still lack T-cell receptor-gamma rearrangements.

Haematopoietic precursors first colonizing the avian embryonic thymus are derived from the intraembryonic sites located around the dorsal aortae. These intraembryonic precursors have previously been demonstrated to include cells that harbour T-cell progenitor capacity and express the Ikaros transcription factor, known to be a prerequisite for lymphocyte development. In this study, we further evaluated the properties of these prethymic cells. We show that early intraembryonic cells and prethymic progenitors already express the GATA-3 transcription factor. The chicken homologue of T-cell factor-1, chTcf, is also detected in cells isolated from the avian para-aortic region. However, these intraembryonic cells retain their T-cell receptor gamma loci in germline configuration. Interestingly, chTcf was found to express different alternatively spliced isoforms during early ontogeny and thymic T-cell development, which indicates developmentally regulated expression of chTcf variants. Taken together, these results demonstrate that, although the avian prethymic progenitor cells express T-lineage-associated transcription factors, they have not yet undergone TCR rearrangements. It is therefore suggested that activation of lineage-associated genes is an early event in the generation of haematopoietic progenitor cells during ontogeny.

Amino Acid Sequence↗
PubMed2000

Pax-5 and EBF are expressed in committed B-cell progenitors prior to the colonization of the embryonic bursa of fabricius.

The committed B-cell precursors developing from hemopoietic stem cells have been considered to differentiate through a common lymphoid progenitor stage in the mouse. In the chicken B-cell system, however, the committed B-cell progenitors burst as a single wave prior to the bursal colonization and most likely as direct descendants of hemopoietic stem cells. In the present report we show that prebursally committed B-cell progenitors specifically express early B-cell factor (EBF) and Pax-5 transcription factors. In addition we show that the expression of these and other B-lineage-associated transcription factors starts early in the chicken ontogeny. Altogether our findings strongly support the model of early delineation of B- and T-cell development and do not support the existence of common lymphoid stem cells.

Animals↗
PubMed1999

The evolutionarily conserved avian Aiolos gene encodes alternative isoforms.

Aiolos is an Ikaros-related lymphoid regulatory protein involved in B cell development and function. To evaluate the role of Aiolos in avian B lymphopoiesis, we have cloned and characterized the first non-mammalian Aiolos ortholog in the avian. In sharp contrast to the avian Ikaros, expressed already at the multipotential stage and prior to the colonization of the lymphoid rudiments, Aiolos transcripts were not expressed in early ontogeny and were first detected in cells isolated from the embryonic bursa of Fabricius and thymus. In accordance with Ikaros, the avian Aiolos is also highly related to the mammalian homolog, thus suggesting an evolutionarily conserved function in lymphocyte development. Interestingly, in contrast to the mammalian Aiolos, at least one alternatively spliced form of avian Aiolos is detected in addition to the primary full-length transcript. Both of these alternate transcripts are expressed in bursa, thymus and peripheral lymphoid cells, and no major differences in the expression were detected during lymphocyte development. Furthermore, avian Aiolos is clearly expressed at various stages of B cell development, thus supporting recent evidence for the importance of Aiolos in B cell development and function.

Alternative Splicing↗
PubMed1999

Synovial fluid T cells from patients with rheumatoid arthritis are refractory to the T helper type 2 differentiation-inducing effects of interleukin-4.

The balance between T helper type 1 (Th1) and Th2 cytokines is thought to be important in the initiation and outcome of autoimmune diseases. The goal of the present study was to compare the production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) by synovial fluid (SF) and peripheral blood (PB) CD4+ and CD8+ cells from patients with rheumatoid arthritis (RA) using three-colour immunofluorescence staining and flow cytometry, and to investigate the capacity of IL-4, IL-10 and IL-12 to modify the cytokine production profile of SF T cells. The frequency of IFN-gamma-producing CD4+ and CD8+ cells was significantly increased in SF when compared with PB. In contrast to IFN-gamma, the expression of IL-4 in SF and PB T cells was comparable. The majority of IL-4-producing cells in SF belonged to Th0/T cytotoxic (Tc) type 0 phenotype, whereas there were significantly more Th2/Tc2 cells in PB than in SF. Interestingly, IL-4 was unable to induce differentiation of non-adherent SF mononuclear cells (SFMC) into Th2 cells, whereas PB mononuclear cells (PBMC) under similar culture conditions differentiated into cells producing high levels of IL-4, IL-10 and IL-13. In contrast, there were no major differences in the effects of IL-10 and IL-12 on the cytokine production profile of SFMC when compared with PBMC. Taken together, the present results suggest that SF T cells from patients with RA are terminally differentiated into Th1/Tc1-like phenotype, and Th2/Tc2 differentiation-inducing agents, such as IL-4, may not be able to reverse the inflammatory process occurring in the joints.

Adult↗
PubMed1999

Characterization of prethymic progenitors within the chicken embryo.

The thymic primordium in both birds and mammals is first colonized by cells emerging from the intra-embryonic mesenchyme but the nature of these precursors is poorly understood. We demonstrate here an early embryonic day 7 prethymic population with T lymphoid potential. Our work is a phenotypic analysis of, to date, the earliest embryonic prethymic progenitors arising in the avian para-aortic area during ontogeny. The phenotype of these cells, expressing the cell surface molecules alpha2beta1 integrin, c-kit, thrombomucin/MEP21, HEMCAM and chL12, reflects functional properties required for cell adhesion, migration and growth factor responsiveness. Importantly, the presence of these antigens was found to correlate with the recolonization of the recipient thymus following intrathymic cell transfers. These intra-embryonic cells were also found to express the Ikaros transcription factor, the molecular function of which is considered to be prerequisite for embryonic lymphoid development.

Animals↗
PubMed1998

Expression of chL12 surface antigen is associated with cell survival in the avian bursa of Fabricius.

During B-cell development in the avian bursa of Fabricius most of the developing B cells die by apoptosis and only a minority survive to emigrate into the periphery. Recently, it has been shown that when developing bursal cells become mature and ready to migrate they start to express chL12 antigen. The expression of this cell-surface molecule was found to be associated with the survival of the bursal cells both after in vitro culture and after in vivo cyclophosphamide (CY) treatment. The frequency of early apoptotic cells in freshly isolated bursal cells was found to be high. The high susceptibility of these cells to apoptosis is in line with the finding of low bcl-2 mRNA expression. We conclude that expression of avian chL12 antigen is associated with the survival of bursal cells.

Animals↗
PubMed1998

Antigenic phenotype of early intra-embryonic lymphoid progenitors in the chicken.

The stem cells for the definitive haematopoiesis are derived from intra-embryonic sources originally described in an avian model and later also in mammals. However, the molecular make-up of the early embryonic haematopoietic progenitors is not yet clearly defined. We have recently characterized the phenotype of prethymic intra-embryonic progenitors capable of thymic colonization. Here we studied the ontogeny of cell-surface antigens HEMCAM, alpha2beta1 integrin, thrombomucin, chL12 and c-kit and their co-expression on prethymic T-cell progenitors. The early intra-embryonic expression of avian B-cell antigen chB6 was also demonstrated on cells derived from the intra-embryonic areas. We suggest that in the chicken, embryonic B-cell progenitors segregate earlier than T-cell progenitors in the differentiation of multipotent haematopoietic stem cells to committed progenitors.

Animals↗
PubMed1998

Antioestrogens enhance tumour necrosis factor receptor 2 (TNF-R2) expression and TNF-R2-mediated proliferation in activated T cells.

In the present study we demonstrate that the non-steroidal antioestrogens toremifene and tamoxifen inhibit mitogen-induced proliferation and up-regulation of tumour necrosis factor (TNF) receptor family molecules on peripheral blood T cells. In activated T cells, however, toremifene and tamoxifen increase the surface expression of tumour necrosis factor receptor 2 (TNF-R2). This up-regulation is functionally important as TNF-R2-mediated proliferation is significantly enhanced in antioestrogen-treated activated T cells. The regulation of TNF-R2 expression in activated T cells seems to involve the c-Jun amino terminal kinase (JNK) pathway, as activation of JNK with anisomycin down-regulates TNF-R2. In activated T cells toremifene clearly inhibits phorbol 12-myristate 13-acetate (PMA)-induced JNK activity, suggesting that the JNK pathway may also be involved in the up-regulation of TNF-R2 expression by antioestrogens. Taken together, the enhancement of TNF-R2 expression and TNF-R2-mediated proliferation in activated T cells represents a novel feature for the effects of antioestrogens. The inhibitory effects of toremifene on the JNK pathway demonstrates that antioestrogens can influence not only cell growth, but also a variety of other cellular responses by inhibiting protein kinase C (PKC).

Antibodies↗
PubMed1998

Costimulatory function of CD28 in avian gammadelta T cells is evolutionarily conserved.

CD28 costimulatory signals are required for T-cell proliferation and lymphokine production. In this work, the functional conservation of CD28 was studied in avian gammadelta T cells. The avian CD28 molecule is expressed on all alphabeta T cells and is capable of giving a costimulatory signal. Most peripheral gammadelta T cells are CD28 negative; however, we identified a CD28-positive gammadelta T-cell subset from peripheral blood comprising about 12% of gammadelta T cells. The peripheral CD28+ gammadelta T-cell subset included all CD8+ gammadelta T cells known to be a responding subset during activation. After polyclonal activation, the frequency of CD28+ gammadelta T cells was increased and the activation also up-regulated CD5, CD25 and major histocompatibility complex (MHC) class II molecules. These changes were detected after both polyclonal and antigen-specific T-cell activation. In addition, we also showed that CD28 can give a costimulatory signal to gammadelta T cells and that this signal leads to up-regulation of IL-2 and bcl-x transcripts. These results indicate that the function of CD28 is evolutionarily conserved and can already be detected in avian gammadelta T cells.

Animals↗
PubMed1998

Interleukin-10 inhibits the capacity of synovial macrophages to function as antigen-presenting cells.

OBJECTIVE: We have investigated the effects of interleukin (IL)-10, IL-4 + granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha) on the phenotype and antigen-presenting capacity of synovial fluid (SF) macrophages from patients with rheumatoid arthritis. METHODS: The effects of IL-4, IL-10, GM-CSF and TNF-alpha on the expression of surface antigens on SF macrophages were studied using flow cytometry. The effects of these cytokines on the capacity of SF macrophages to activate T cells was investigated using the allogeneic mixed lymphocyte reaction (MLR). RESULTS: IL-10 reduced the expression of CD40, CD86 and HLA-DR, and increased the expression of CD14, on SF macrophages. IL-10 had no effect on the expression of CD80. Importantly, these effects of IL-10 on the phenotype of SF macrophages appear to have functional consequences, because cells incubated with IL-10 had a significantly reduced capacity to activate T cells in MLR. The effects of IL-4, GM-CSF and TNF-alpha were generally opposite to those observed in response to IL-10. IL-4 + GM-CSF, a combination of cytokines known to induce differentiation of dendritic cells, increased the expression of CD40, CD80 and CD86, and decreased the expression of CD14 on SF macrophages. Accordingly, IL-4 + GM-CSF increased the capacity of SF macrophages to activate T cells in MLR. IL-10 inhibited the effects of IL-4 + GM-CSF on SF macrophages. CONCLUSIONS: IL-10 inhibits the antigen-presenting capacity of SF macrophages, which further emphasizes the anti-inflammatory potential of IL-10 in RA. Importantly, IL-10 is able to downregulate the APC function of SF macrophages even when they are efficiently activated.

Adult↗
PubMed1997

A novel peripheral CD4+ CD8+ T cell population: inheritance of CD8alpha expression on CD4+ T cells.

In this study we show the inheritance of a CD4+ CD8+ peripheral Tcell population in the H.B15 chicken strain. A large proportion of alphabeta T cells in peripheral blood (20-40%), spleen (10-20%) and intestinal epithelium (5-10%) coexpress CD4 and CD8alpha, but not CD8beta. CD4+ CD8alpha alpha cells are functionally normal T cells, since they proliferate in response to mitogens and signals delivered via the alphabeta T cell receptor as well as via the CD28 co-receptor. These cells induce in vivo a graft versus host-reaction, providing further evidence for their function as CD4+ T cells. The CD4+ CD8alpha alpha T cell population was found in 75% of the first progeny and in 100% of further progenies, demonstrating that coexpression of CD4 and CD8 on peripheral T cells is an inherited phenomenon. In addition, cross-breeding data suggest a dominant Mendelian form of inheritance. The hereditary expression of CD8alpha on peripheral CD4+ T cells in chicken provides a unique model in which to study the regulation of CD4 and CD8 expression.

Animals↗