Radiosensitivity of T-lymphocyte subpopulations.
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Biomedical subjects
Publications and source records attributed to H Blomgren.
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Bestatin, which is a chemically well-defined immunomodulator, was examined for its possible influence on various monocyte functions. It was observed that pretreatment of separated human blood monocytes with Bestatin did not change their chemotactic or random migration. In addition, the capacity of monocytes to reduce nitroblue tetrazolium or to inhibit growth of Chang cells was unchanged by Bestatin. Phagocytosis of yeast particles, however, was increased by pretreatment of monocytes with Bestatin in vitro and it was observed that oral administration of Bestatin to cancer patients augmented the phagocytic activity of blood monocytes in vitro.
A group of 17 patients, having undergone modified radical mastectomy for breast cancer, received 12 cycles of chemotherapy with methotrexate, 5-fluorouracil, and chlorambucil during 17 months. The number of circulating T and non T lymphocytes, as defined by E, EAC, and ME rosette formation, were reduced during treatment. The Non-T lymphocytes, however, were reduced to the highest relative extent. Relative phytohemagglutinin and mixed lymphocyte culture responses of the cells decreased, whereas purified protein derivative responses were unchanged. Serum concentrations of IgM were reduced, but IgA and IgG concentrations were unchanged or slightly increased. Antibody titres to morbilli and herpes simplex were not changed, whereas the antibody activity against cytomegalovirus (CMV) increased in several seropositive patients. None of these patients, however, developed signs of a CMV infection.
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Treatment of cancer patients with Bestatin, a new immunomodulator increases the frequency of peripheral lymphocytes forming rosettes with sheep red blood cells (SRBC). This study has shown that treatment of lymphocytes from healthy donors with Bestatin in vitro increases the frequency of such cells and there is a slight decrease of C'3-receptor bearing cells. The proportions of TM and TG cells were not significantly changed. The results indicate that the increased frequency of SRBC-binding cells during Bestatin medication is not due to a mobilisation of T-cells but rather to an improved binding capacity of certain T-cells for SRBC.
Various interferon (INF) preparations were examined for their capacity to influence the poke weed mitogen (PWM) induced release of IgM and IgG by human lymphocytes in vitro. Variable results were obtained when partially purified preparations of leukocyte IFN-alpha were added at the beginning of the culture period: In some experiments Ig production increased and in others it decreased. The addition of a pure preparation of IFN-beta significantly augmented Ig release. It is suggested that substances other then IFN in impure IFN preparations may interfere with the PWM triggered Ig-release.
Bestatin, a chemically well-defined immunomodulator, was tested for its capacity to interfere with PWM-induced Ig synthesis of peripheral lymphocytes from healthy donors. It was observed that secretion of IgA, IgG and IgM was impaired when Bestatin was present in the cultures. Serum Ig concentrations and antibody activities of IgG class to cytomegalovirus, herpes simplex and morbilli virus were examined in cancer patients who were treated with 30 mg of Bestatin daily for 1-21 weeks. These values remained constant during Bestatin treatment indicating that antibody secretion in vivo was not affected.
Human interferon (IFN) was examined for its capacity to modify the phytohaemagglutinin (PHA)-triggered release of mitogenic factors (MF) from human lymphocytes in vitro. It was observed that the presence of partially purified leukocyte IFN (IFN-alpha) during the PHA pulsing of lymphocytes increased their subsequent release of factors which were mitogenic for fractionated T cells. A similar effect was also observed when lymphocytes were exposed to IFN-alpha prior to PHA pulsing. The possibility that substances in the IFN preparations other than IFN are responsible for the above effect is ruled out by the finding that a pure fibroblast IFN (IFN-beta) preparation also augmented the MF release by PHA-pulsed lymphocytes.
Blood lymphocyte reactivity to purified protein derivative of tuberculin (PPD) and phytohaemagglutinin (PHA) was examined in 62 patients with breast carcinoma who received postoperative adjuvant radiation therapy or cyclic chemotherapy with chlorambucil, methotrexate and 5-fluorouracil. Both treatments impaired the immunologic reactivity of blood lymphocytes as measured by PPD and PHA stimulation in vitro. Radiation therapy seemed to cause more profound and protracted suppression of the PPD response than chemotherapy.
The blood lymphocyte population was monitored in 6 patients with advanced malignant tumors who were treated with large doses of a new cytotoxic drug termed pepleomycin. It was observed that the size of the cell population, its cellular composition, mitogen stimulations and natural killer activity did not change in any consistent ways during or after treatment. It is concluded that pepleomycin does not directly affect the lymphocytic population.
Peripheral lymphocyte subpopulations were examined in 37 women with breast carcinoma who were postoperatively randomized to adjuvant local radiation therapy or cyclic treatment with 5-Fluorouracil, Methotrexate and Chlorambucil. Both T and non-T lymphocyte counts were reduced but the latter subpopulation was reduced to the highest relative extent in both groups of patients. Following radiation therapy the non-T cells repopulated more rapidly than the T cells, whereas the repopulation seemed to be the reverse in patients treated with chemotherapy.
The effect of human interferon (IF) on lectin-dependent cellular cytotoxicity (LDCC) was studied in vitro. Using chicken erythrocytes as target cells in a 40h assay IF was found to inhibit this reaction at concentrations of 1,000 IF units/ml. When tumor cells were used as targets in a 4 h assay IF caused an increase in the cytotoxic activity of lymphocytes in the presence of PHA. However, when the spontaneous cytotoxic activity was subtracted from this value no major effect of IF on LDCC could be observed.
A new chemically well-defined immunomodulator termed Bestatin was examined for its capacity to interfere with the release of factors from PHA pulsed human peripheral lymphoid cells which are mitogenic for T-cells. The presence of Bestatin, at Concentrations of 0.01-100 microgram/ml, during PHA-pulsing significantly enhanced the subsequent release of mitogenic factors. The highest increase, fourfold, was observed using 10 microgram/ml of Bestatin, Treatment of lymphoid cells with Bestatin alone or pretreatment with this compound before PHA pulsing did not significantly change the subsequent release of these lymphokines.
Bestatin, which is a chemically well-defined immunomodulator, was tested for its capacity to change certain functions of human granulocytes from healthy donors in vitro. Pretreatment of granulocytes with Bestatin enhanced their spontaneous migration as well as their migration in the presence of chemotactic stimuli. Moreover, Bestatin treatment augmented the ingestion of yeast particles but it did not change the oxidative metabolism of the cells as measured by their capacity to reduce nitroblue tetrazolium.
Blood lymphocyte subpopulations from 10 untreated patients with Hodgkin's disease and 10 healthy controls were examined with respect to their radiosensitivity in vitro. T-cells (E-rosette forming) were more sensitive in 7 out of the 10 patients whereas these cells appeared to be relatively radioresistant in all control persons. However, a subpopulation of T-cells forming "active" E-rosettes, was relatively resistant in 9 of the patients and all of the controls. Non-T-cells (EAC-rosette forming) were equally sensitive in patients and in controls.
The effect of daily injections of 3 x 10(6) units of human leukocyte IF on the spontaneous cytotoxicity of peripheral lymphocytes was studied in 43 patients with a variety of diseases. An increase in spontaneous cytotoxicity was observed 12 to 24 h after the first IF injection with the peak of activity occurring, in most cases, at 24 h. In some patients a decrease in spontaneous cytotoxicity, observed 6 h after the injection, preceded this increase. The increment in spontaneous cytotoxicity was not significantly correlated to preinjection level of cytotoxicity, disease, age, sex, previous therapy, leukocyte counts or proportions of lymphocytes and monocytes. A second injection of IF maintained the spontaneous cytotoxicity at an increased level and during prolonged IF therapy, up to 9 months, the cytotoxicity remained elevated. IF treatment in vitro caused an enhancement of spontaneous cytotoxicity in lymphocytes drawn prior to IF injection. This IF-induced increase in cytotoxicity in vitro was correlated to the increase in cytotoxicity induced by IF in vivo. Six hours after the first IF injection the ability of IF in vitro to enhance spontaneous cytotoxicity was decreased and during prolonged therapy the ability of IF in vitro to enhance spontaneous cytotoxicity remained decreased.
Blood lymphocytes from 10 untreated patients with active Hodgkin's disease were compared with those of 10 cured patients with regard to the responsiveness of the cells to PHA and Con A following in vitro irradiation. Lymphocytes of patients remaining in long-term remission exhibited the same pattern of radiosensitivity as those of healthy donors: there was one relatively radiosensitive cell population and one relatively resistant. The latter cell population was undetectable in patients with an active disease. Reappearance of the radioresistant PHA and Con A reactive cell fractions might thus be associated with remission.