[Treatment with high-dose cytostatic agents].
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Adult↗
Biomedical subjects
O Bruserud
Publications and source records attributed to O Bruserud.
Serum concentrations of tumour necrosis factor-alpha during chemotherapy-induced leukopenia in patients with acute leukaemia and bacterial infections.
Serum concentrations of tumour necrosis factor-alpha (TNF-alpha) increase during septicaemia in previously healthy individuals. To investigate whether a similar increase in TNF-alpha can be seen in severely immunocompromised patients with acute leukaemia and chemotherapy-induced leukopenia, serum TNF-alpha was analysed in leukopenic patients with bacterial infections. Pretherapy serum levels of TNF-alpha were decreased in leukaemia patients compared with healthy controls, and serum TNF-alpha levels showed a further decrease when patients developed chemotherapy-induced leukopenia. When leukopenic patients developed bacterial infections, serum concentrations of TNF-alpha increased. Serum levels of TNF-alpha decreased when clinical signs of infection resolved during antibiotic therapy, but an increase occurred later in parallel with haematopoietic reconstitution.
Adolescent↗
Effects of dipyridamole and R-verapamil on in vitro proliferation of blast cells from patients with acute myelogenous leukaemia.
Cytokine-dependent AML cell proliferation was investigated in 16 patients. Dipyridamole and R-verapamil caused a dose-dependent inhibition of AML cell proliferation, and for both drugs the degree of inhibition was similar when testing various haematopoietic growth factors or growth factor combinations (IL3, G-CSF, GM-CSF, G-CSF + GM-CSF, TNF-alpha + GM-CSF). TNF-alpha alone increased AML cell proliferation for five patients, whereas four patients showed unaltered or decreased proliferation. Independent of this TNF-alpha effect, R-verapamil inhibited proliferation for all AML patients in the presence of TNF-alpha, whereas dipyridamole caused only a weak inhibition.
Adult↗
Cyclosporine A and FK506 show similar immunosuppressive effects on long-term in vitro T-cell proliferation.
Because Cyclosporine A (CsA) is often reported to inhibit only the proliferation of quiescent T-cells and to have much less or no effect on activated proliferating T-cells, the effects of CsA and FK506 on long-term in vitro T-cell proliferation were investigated for alloreactive T-cell clones and clones derived from a leukaemia patient early after allogeneic bone marrow transplantation. Drug effects were tested in the presence of exogenous IL2 or IL2 + IL4 during weekly T-cell activation/restimulation. In the presence of either drug, cloned T-cells were able to respond to a reduced number of restimulations (mitogenic activation, allostimulation) and could undergo fewer cell divisions/population doublings. These effects were seen in the presence of both excess IL2 or IL2 + IL4.
Cell Division↗
Secretion of IL-2, IL-3, IL-4, IL-6 and GM-CSF by CD4+ and CD8+ TCR alpha beta+ T-cell clones derived early after allogeneic bone marrow transplantation.
Secretion of different cytokines may be an important T-cell effector mechanism for bone marrow engraftment, graft versus host disease and graft versus leukaemia effects after allogeneic bone marrow transplantation (BMT). Cytokine secretion and autocrine proliferative capacity of T-cell clones derived from leukaemia patients 3-6 weeks after allogeneic bone marrow transplantation were investigated. Only a minority of post-transplant T-cell clones (23/120; 19%) was capable of undergoing autocrine proliferation. By contrast, 21/65 (32%) normal control clones from the marrow donors derived under the same conditions were autocrine proliferative. All clones were interleukin-2 (IL-2) responsive. A majority (12/17; 71%) of autocrine proliferating post-transplant clones secreted detectable IL-2. Compared with control clones, CD4+ T-cell clones derived early after BMT produced decreased levels of interleukin-4 (IL-4) and interleukin-6 (IL-6), whereas secretion of interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) showed no significant difference. The small number (n = 8) of posttransplant CD8+ clones showed decreased production of IL-3, IL-4 and IL-6 compared with control clones, but normal secretion of GM-CSF. Neither CD4+ nor CD8+ T-cell clones secreted interleukin-7 (IL-7).
Adult↗
IFN-gamma and TNF-alpha secretion by CD4+ and CD8+ TCR alpha beta + T-cell clones derived early after allogeneic bone marrow transplantation.
Secretion of the potentially antileukaemic cytokines IFN-gamma and TNF-alpha was investigated for CD4+ and CD8+ TCR alpha beta + T-cell clones derived from 4 leukaemia patients 3-6 weeks after allogeneic BMT. We investigated cytokine secretion in response to the activation signal accessory cells+phytohaemagglutinin+Interleukin 2. All clones derived after BMT were capable of IFN-gamma and TNF-alpha secretion, and both for CD4+ (n = 96) and CD8+ (n = 8) T cells quantities of IFN-gamma and TNF-alpha were significantly correlated with one another. When comparing the overall results for posttransplant and normal T-cell clones derived from 2 bone marrow donors (n = 65), both CD4+ and CD8+ TCR alpha beta + T-cell clones showed increased IFN-gamma production, and CD4+ but not CD8+ clones showed a decreased TNF-alpha secretion. The results suggest that noncytotoxic T cells derived after allogeneic BMT can produce IFN-gamma and TNF-alpha and may thus be capable of mediating antileukaemic effects.
Adult↗
At least five antigenic epitopes on the streptokinase molecule are recognized by human CD4+ TCR alpha beta+ T cells.
The streptokinase molecule (415 AA) was cleaved at methionine 237, 347 and 370 yielding four polypeptide fragments. Human HLA-class II restricted streptokinase-specific T cell clones and cell lines (CD2+, CD3+, CD4+, CD8-, TCR alpha beta+, TCR gamma delta-) recognized antigenic epitopes on all four fragments AA 1-236, AA 238-346, AA 348-369 and AA 371-415. T cell clones recognizing fragment AA 1-236 were restricted by at least two different HLA-class II elements, this indicating that more than one antigenic epitope can be recognized on this fragment. In addition, two streptokinase-specific T cell clones recognized only the intact molecule and none of the molecular fragments. These two clones probably recognized an antigenic epitope including one of the methionine residues used for molecular cleavage. We conclude that T cell proliferative responses to streptokinase are determined by recognition of at least five different antigenic epitopes distributed along the entire streptokinase polypeptide chain.
Adult↗
CD4+ TCR alpha beta+ T-cell clones derived shortly after allogeneic bone marrow transplantation: theophyllamine and verapamil inhibit proliferation of functionally heterogeneous T-cells.
CD4+ TCR alpha beta+ T-cell clones were prepared from three CML-patients 4-6 weeks after allogeneic bone marrow transplantation and the effects of theophyllamine and verapamil on clonal growth then assessed. Both drugs inhibited PHA-stimulated autocrine proliferation of clones as well as proliferation of clones dependent on exogenous growth factors. Inhibition was seen when using different accessory cells (PBM or BCL) during T-cell activation, and both for IL2- and IL4-dependent proliferation of previously activated T-cells. The isomer R-verapamil inhibited PHA-stimulated proliferation as well as IL2- and IL4-dependent T-cell proliferation. The drugs also inhibited proliferation of CD8+ T-cells. Although the T-cell clones were functionally heterogeneous and were derived from different patients and priming cultures, both drugs inhibited all clones investigated. However, the degree of inhibition varied between different clones.
Aminophylline↗
The effect of disodium cromoglycate on in vitro proliferation of peripheral blood mononuclear cells from allergic and healthy donors.
The effect of disodium cromoglycate on in vitro proliferative responses of peripheral blood mononuclear cells from healthy individuals, allergic patients with moderate serum IgE and patients with atopic dermatitis and high levels of serum IgE was investigated. Peripheral blood mononuclear cells were stimulated with mitogens (phytohaemagglutinin, Concanavalin A), recombinant interleukin-2, calcium ionophore + phorbol 12-myristate 13-acetate, purified protein derivative of tuberculin and allergens. It was possible to induce in vitro specific, allergen-triggered responses only in allergic individuals with moderate serum IgE and not in individuals with atopic dermatitis and high serum IgE. Generally, whenever the stimulatory signal(s) caused a significant proliferative response, disodium cromoglycate inhibited the proliferation. This inhibition was seen for all activation agents and for both healthy and allergic individuals. By contrast, for certain non- or low-responders (both healthy and allergic individuals) disodium cromoglycate seemed to amplify the proliferation to various activation signals. Only non- or low-responder cells derived from atopic dermatitis patients showed a biphasic kinetic response pattern when stimulated with the drug in combination with recombinant interleukin-2, recombinant interleukin-2 + ionophore or specific allergens.
Calcimycin↗
IL2- and IL4-dependent proliferation of T-cell clones derived early after allogeneic bone marrow transplantation: studies of patients with chronic myelogenous leukaemia.
In an attempt to explore T-cell functions shortly after allogeneic bone marrow transplantation more fully, IL2- and IL4-dependent proliferation was assessed on CD4+ TCR alpha beta+ T-cell clones derived 4-6 weeks after transplantation. Both allogeneic pooled peripheral blood mononuclear cells and Epstein-Barr virus-transformed B-cell lines (BCL) could function as accessory cells (AC) for PHA activation of T-cell clones. Although minimal clonal proliferation was seen when the T-cell activation signal was BCL+PHA+IL4, a majority of the clones could undergo IL4-dependent proliferation after previous activation with AC+PHA+IL2. For certain clones, IL4 also showed an additive effect with IL2. Thus, IL4 was a growth factor for a majority of the investigated posttransplant T-cell clones, and in vivo modulation of IL4-dependent T-cell functions may thus become a future therapeutic possibility to enhance graft-versus-leukaemia effects in bone marrow transplant recipients.
Antigen-Presenting Cells↗
Effect of dipyridamole, theophyllamine and verapamil on spontaneous in vitro proliferation of myelogenous leukaemia cells.
Dipyridamole strongly inhibited spontaneous in vitro proliferation of peripheral blood mononuclear cells from patients with acute myelogenous leukaemia (n = 9), chronic myelogenous leukaemia in first chronic phase (n = 4) and blast phase (n = 1). Theophyllamine and verapamil also inhibited proliferation of leukaemia cells from all patients except the CML patient in blast phase where only minimal inhibition was seen. Only dipyridamole caused strong inhibition in concentrations corresponding to the therapeutic serum level, and this inhibition was not influenced by the presence of high levels of interleukin 2.
Aminophylline↗
Tumor-specific antigens revisited: presentation to the immune system of fusion peptides resulting solely from tumor-specific chromosomal translocations.
Adaptive immune responses depend upon recognition by lymphocytes-T of short polypeptide sequences bound to major histocompatibility complex (MHC) molecules. Since endogenous intracellular proteins can be presented to the immune system in this way, any tumor-specific structure may function as a potentially tumor-specific antigen. Fusion proteins arising as a result of chromosomal translocations provide good candidates for novel tumor-specific antigens recognizable by the host immune system. Recent molecular cloning data have demonstrated the existence of mRNAs encoding several different potential tumor-specific fusion proteins in both acute and chronic leukemias, and analysis of a number of these sequences suggests the presence of a newly defined amino acid motif associated with MHC-binding and T cell recognition. Preliminary data suggest the possibility of generating in vitro lymphocyte-T responses to synthetic peptides representing the chimeric sequences. It remains to be seen whether tumor cells themselves can be recognized by lymphocytes-T in vitro and in vivo, and, if so, how leukemia cells escape such immune surveillance in vivo.
Amino Acid Sequence↗
CD4+ TCR alpha beta+ T-cells developing after allogeneic bone marrow transplantation in patients with chronic myelogenous leukaemia. Dipyridamole inhibits functionally heterogeneous T-cell clones.
Dipyridamole inhibited the proliferation of functionally heterogeneous CD4+ TCR alpha beta+ T-cell clones prepared from CML-patients 4-6 weeks after allogeneic bone marrow transplantation. The effect was seen when testing concentrations corresponding to the therapeutic serum level. Dipyridamole caused a dose-dependent inhibition of PHA-stimulated proliferation both for clones dependent on exogenous IL2 and clones undergoing autocrine proliferation. The inhibition was seen when using different accessory cells (PBM or BCL), and also when dipyridamole was present during IL2- or IL4-dependent proliferation of activated T-cells. The effect of dipyridamole was also investigated for 76 T-cell clones (76 CD4+ and 7 CD8+ clones) prepared by different cloning procedures from three patients. Although these clones were heterogeneous with regard to cytotoxic function, lymphokine production or lymphokine responsiveness, dipyridamole inhibited IL2-dependent proliferation of all clones. In addition dipyridamole inhibited proliferation of CML cells.
Adult↗
Cytotoxic and proliferative functions of T lymphocyte clones derived very shortly after allogeneic bone marrow transplantation.
In a search for mechanisms of potential graft-versus-leukaemia (GVL) activity after allogeneic bone marrow transplantation (BMT), peripheral lymphocytes from five patients (four chronic myeloid leukaemia, one acute lymphoblastic leukaemia) 24-39 days post-transplant were precultured with pretransplant host leukaemia cells and then cloned by limiting dilution with interleukin-2 (IL-2). Clones obtained were exclusively CD3+ CD56-, carried the alpha/beta form of the T cell receptor for antigen, and were mostly (88% of 138) CD4+. None of 143 clones, including CD8+ clones, convincingly lysed host pretransplant cells, although 35 (24.5%) manifested lytic potential in lectin-mediated cytotoxicity assays. Measuring the proliferative responses of 118 of these clones in the presence of exogenous IL-2 revealed that a small number of clones reacted more strongly to host leukaemia than to unrelated leukaemias or B lymphoblastoid cell lines. In the two cases tested, the donor's untransplanted lymphocytes cloned under the same conditions as post-transplant cells did not generate any clones reacting preferentially with host leukaemia cells. These results may suggest that some T cells appearing shortly after allogeneic BMT could potentially mediate anti-leukaemia activity not associated with cytolysis of target cells.
Antigens, Differentiation, T-Lymphocyte↗
[Allergic reactions during streptokinase therapy].
The article reviews immunological reactions to streptokinase. The humoral immune response to streptokinase involves antibodies of different subclasses, including IgG, IgM, and IgE. A T cell response to streptokinase can also be demonstrated, involving both CD4 and CD8 positive cells. Streptokinase therapy involves increased risk of all kinds of allergic reactions, including urticaria, bronchial obstruction, shock and serum sickness.
Humans↗
The additive effect of certain drugs on the cyclosporine A inhibition of human T-cell proliferation. Studies using theophyllamine, warfarin, verapamil and dipyridamol.
The inhibitory effect of Cyclosporine A (CsA) when combined with theophyllamine, warfarin, verapamil or dipyridamol on in vitro proliferation of human T lymphocyte was investigated. All drugs caused an additional inhibition of PHA activation compared with CsA alone, also when the CD8-negative and -positive subsets were tested separately. This effect was dose-dependent for all drugs. Theophyllamine, verapamil and warfarin had to be added early during PHA-stimulated T-cell activation to cause maximal inhibition. Also when testing the proliferative response in mixed lymphocyte cultures, the drugs showed a dose-dependent additional inhibition compared with CsA alone. CsA alone caused no inhibition of lymphokine-dependent growth of T-cell lines, whereas all four drugs caused a weak inhibition in this test system.
Aminophylline↗
The proliferative response of peripheral blood mononuclear cells to streptokinase. A study of patients receiving a single intravenous infusion of purified streptokinase.
In vitro proliferative PBM responses were investigated for 26 patients with and 5 patients without acute myocardial infarction. All patients were initially treated with streptokinase (1.5 MIU infused for 1 hour). Five weeks after the disease increased responses to streptokinase, PPD and PHA were seen; but only for streptokinase had original nonresponders become responders (7 out of 14 nonresponders). The increased responsiveness to streptokinase could be detected five days after antigen infusion, and CD-2 positive cells constituted a major part of the proliferating PBM population. The responses after antigen infusion varied within a wide range both for patients with and without myocardial infarction.
Adult↗
Reduction of coronary artery bypass graft occlusion by dipyridamol--is immunosuppression important?
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Coronary Artery Bypass↗