Biomedical subjects

M Micksche

Publications and source records attributed to M Micksche.

At least 91 records · Page 5Linked to original sources

PubMed1984

In vitro modulation of human natural killer cell activity by interferon: generation of adherent suppressor cells.

The in vivo and in vitro effects of human alpha-interferon (IFN) on blood natural killer (NK) cell activity were studied in patients with malignant melanoma. The initial response to an i.m. injection of IFN was a depression of blood NK cell activity, being detectable at 4 h and reaching a nadir at 12 h. Blood NK cell activity returned to or exceeded pretreatment levels within 24 h. The frequency of large granular lymphocytes among peripheral blood lymphocytes (PBL), however, remained unchanged during the first 24 h of IFN treatment. In a single cell cytotoxicity assay in agarose the number of lymphocytes forming conjugates with K562 target cells was not affected at 12-h points of IFN treatment, while the frequency of lytic conjugates with dead target cells was decreased by 12 h. Thus, the number of active NK cells was reduced by IFN administration. While in vitro exposure to IFN resulted in an augmentation of NK cell activity of PBL from untreated patients, IFN failed to enhance the activity of PBL obtained 12 h post IFN injection. When PBL obtained 12 h after IFN injection were cultured overnight, they recovered their responsiveness to NK-boosting effects of IFN. Blood monocytes obtained at 12-h points from IFN-treated patients suppressed IFN-induced enhancement of NK cell activity, although these monocytes did not inhibit the base line level of NK cell activity. In contrast, the streptococcal preparation OK432 was able to augment NK cell activity of PBL obtained 12 h post IFN administration and of control PBL even in the presence of suppressor monocytes. PBL obtained 24 h post IFN injection expressing enhanced NK cell activity were also unresponsive to IFN in vitro. However, monocytes obtained 24 h after IFN injection were no longer able to inhibit IFN-induced augmentation of NK cell activity. These results indicate that in vivo administration of IFN-alpha to cancer patients results in rapid and transient generation of suppressor monocytes capable of inhibiting IFN-dependent development of functional NK cell activity, which could be responsible for the initial and transient decline in blood NK cell activity.

Cells, Cultured↗

PubMed1984

Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells.

Adherent cells from carcinomatous pleural effusions of lung cancer patients were tested for their ability to suppress natural killer (NK) cell activity, and the mechanism involved in the suppression of NK cell activity was determined. Adherent effusion cells (AEC) were isolated from malignant pleural effusions of patients by centrifugation discontinuous Ficoll-Hypaque gradients and adherence to serum-coated plastic dishes, and large granular lymphocytes (LGL) were purified from the peripheral blood of normal individuals by centrifugation on discontinuous Percoll gradients and further depletion of high-affinity sheep erythrocyte rosette formation. LGL-mediated lysis of K562 cells was suppressed when LGL were cultured with AEC for 20 h, then washed and tested in a 4-h 51Cr release assay. More profound suppression of NK cell activity was observed when cytotoxicity was assayed in flat-bottomed wells rather than in round-bottomed wells. Cytotoxicity assays conducted at the single cell level in agarose revealed that the frequency of LGL binding to K562 cells and of dead conjugated target cells was reduced after overnight contact with AEC. In agarose microdroplet assays, functional LGL from normal donors exhibited definitive motility, expressing polarized shape. In contrast, a small number of LGL with non-polarized configuration migrated from the agarose droplet after overnight culture with AEC. These results indicate that functionally suppressed NK cells lose their motility, binding capacity and killing activity, which could be responsible for the suppression of NK cell activity by AEC.

Cell Adhesion↗

PubMed1984

The value of the DNCB test in bladder cancer. Pretreatment evaluation of immune function and 5-year follow-up of patients with urinary bladder cancer.

In 68 patients with histologically verified tumors of the urinary bladder, cell-mediated and humoral immune parameters were investigated before therapy and the results were re-evaluated after a 5-year observation period in order to correlate them with relapse rate and survival time. Skin test reactivity, as measured with recall antigens (tuberculin, streptokinase-streptodornase, mumps, toxoplasmin and candidin), and serum levels of immunoglobulins do not differentiate between levels of invasion and grade of malignancy. However, it was found that patients with tumors of high grades of invasiveness and malignancy were anergic to the primary skin test antigen dinitrochlorobenzene (DNCB). Furthermore, a correlation between anergic reactivity to the DNCB test and absence of local inflammatory reactions at the tumor site was detected, showing that patients with a negative DNCB challenge test were those in whom no immunocytes could be detected in the intra- and peritumoral area. Survival time and incidence of relapse were also correlated with initial skin test reactivity to DNCB, i.e. all patients with tumor stage pT3 and skin test anergy developed recurrences and died within the 5-year observation period. The correlation between morphological inflammatory criteria and immunological parameters detected in patients with advanced tumor stages should therefore be taken into consideration when taking therapeutic decisions at the time of diagnosis.

Aged↗

PubMed1983

Lysis of fresh human tumor cells by autologous large granular lymphocytes from peripheral blood and pleural effusions.

Human lymphocytes and their subpopulations from the peripheral blood and pleural effusions of cancer patients were tested for cytotoxicity against fresh tumor cells isolated from carcinomatous pleural effusions of the same patients. Fresh tumor cells were relatively resistant to lysis by autologous unseparated lymphocytes in a 4 h Cr-release assay. Positive reactions were recorded in 10 of 38 blood samples and 10 of 37 effusion specimens. Purification of large granular lymphocytes (LGL) by discontinuous Percoll gradient centrifugation resulted in enhancement of cytotoxic activity against autologous tumor cells and K562 cells, with no reactivity in LGL-depleted small T-lymphocyte populations. Significant lysis of effusion tumor cells by autologous LGL was observed in 15 of 22 blood specimens and 15 of 21 effusion samples. Further depletion of high-affinity sheep erythrocyte rosetting cells from Percoll-purified LGL populations gave an increase in autologous tumor-killing activity. Depletion of LGL/K562 conjugates from LGL populations decreased lysis of autologous tumor cells and K562 cells. Effusion tumor cells that were susceptible to lysis by allogeneic normal LGL were also killed by autologous LGL, and effusion tumor cells resistant to lysis by allogeneic NK cells were not lysed by autologous LGL. In a single-cell cytotoxicity assay in agarose, 4-26% LGL bound autologous tumor cells and 0.2-5% LGL killed these target cells, while 12-45% LGL bound K562 cells and 2-20% LGL lysed them. These results indicate that cytotoxic potential for autologous effusion tumor cells is present in the peripheral blood and pleural effusions of cancer patients; it is strongly associated with a minor proportion of LGL and restricted to the cell population that can lyse NK-sensitive K562 cells.

Adult↗

PubMed1983

Intrapleural administration of OK432 in cancer patients: activation of NK cells and reduction of suppressor cells.

Twelve patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) administration of OK432 on day 0 and the effects of i.pl. OK432 on natural killer (NK) cell activity were followed on day 7. Two patients showed no clinical evidence of therapeutic benefit from i.pl. OK432. In the other 10 patients, pleural effusions and/or tumor cells in the effusions had decreased or disappeared by day 7. NK cell activity was markedly low or absent in pleural effusions of untreated patients due to the presence of adherent effusion cells capable of suppressing the maintenance and interferon-induced augmentation of NK cell activity. I.pl. injection of OK432 resulted in enhancement of NK cell activity and abrogation of NK suppressor cell activity in the effusions. On the other hand, blood NK cell activity was not consistently altered by i.pl. OK432. In vitro treatment of effusion mononuclear cells from untreated patients with OK432, but not with interferon, augmented NK cell activity. In addition, adherent effusion cells of untreated patients lost their NK suppressor function following in vitro OK432 treatment. These results suggest that i.pl. administration of OK432 will result in augmentation of NK cell activity and reduction of NK suppressor cell activity in pleural effusions, which could be responsible for the antitumor activity of i.pl. OK432.

Adenocarcinoma↗

PubMed1983

Lysis of fresh human tumor cells by autologous peripheral blood lymphocytes and pleural effusion lymphocytes activated by OK432.

Lymphocytes from peripheral blood (PBL) and from pleural effusions (PEL) of cancer patients were tested for cytotoxicity against tumor cells freshly isolated from carcinomatous pleural effusion of the same patient. Significant lysis of autologous tumor cells was recorded for 4 of 28 PBL samples and for 5 of 28 PEL cases when investigated in a 4-hour 51Cr release assay. In vitro treatment of lymphocytes for 20 hours with the streptococcal preparation OK432 resulted in an induction or augmentation of cytotoxicity against autologous tumor cells in 21 of 28 PBL and PEL specimens. OK432-induced cytotoxicity required active cell metabolism, RNA and protein syntheses, but not DNA synthesis of lymphocytes. Supernatants of OK432-stimulated lymphocytes, and interferon and interleukin 2 failed to induce autologous tumor killing. Nylon wool-nonadherent lymphocytes were involved in both spontaneous and OK432-induced lysis of fresh autologous tumor cells. OK432-activated lymphocytes from normal donors and cancer patients caused lysis of fresh allogeneic tumor cells and also K562 cells.

Adenocarcinoma↗

PubMed1983

Chemotactic properties of partially purified human epidermal cell-derived thymocyte-activating factor (ETAF) for polymorphonuclear and mononuclear cells.

Human epidermal cell thymocyte-activating factor (ETAF) derived from either normal epidermal cells or a squamous cell carcinoma cell line has recently been shown to be a low m.w. protein that is indistinguishable from human macrophage-derived interleukin 1 (IL 1). As with human IL 1, human ETAF elutes from Sephadex S-200 gel in two major peaks at m.w. 70,000 to 40,000 and m.w. 25,000 to 12,000. Rechromatography of the higher m.w. fraction of ETAF yielded some of the lower m.w. activity, and chromatofocusing of high m.w. ETAF yielded the same three isoelectric points as the lower m.w. ETAF. Partially purified human ETAF as well as IL 1 were chemotactic for polymorphonuclear and mononuclear leukocytes. In addition, exposure of PMN to ETAF stimulated increased metabolic activity as demonstrated by greater reduction of intracellular nitroblue tetrazolium. Therefore, this study lends further support for an important role of ETAF in the pathogenesis of inflammatory skin diseases.

Chemotaxis, Leukocyte↗

PubMed1982

[Immunologic stimulation with vitamin A in advanced cervix cancer].

For treatment of patients with inoperable cervical cancer (FIGO III) a randomized trial has been initiated. Patients were randomized to receive either conventional irradiation therapy together with vitamin A palmitate (1.5 mill. I.U./day; total dose: 30 mill. I.U.), applied orally, or irradiation alone. When lymphocyte reactivity to PHA (maximum response during therapy) was compared within the groups, it was found, that 66% of the patients who received irradiation combined with vitamin A palmitate, showed an increase in their blastogenic response, while in irradiated patients without vitamin A palmitate a response was seen only in 33%. This difference being statistically significant in comparison to pretreatment values. From immunological data it can be concluded, that vitamin A has an effect on functional response on T-cells. Concerning the clinical outcome, after an observation period of 12 months relapse rates were lower in the vitamin A group, but not significantly reduced. Therefore further follow up is warranted.

Adjuvants, Immunologic↗

PubMed1982

Natural killer cell activity in patients with multiple sclerosis: interferon and plasmapheresis.

Peripheral blood lymphocytes from patients with multiple sclerosis (MS) were studied for natural killer (NK) cell activity and reactivity to interferon. NK activity determined at the same time in a 4-hr chromium-51 release assay using K562 target cells was significantly lower in MS patients than in controls. In-vitro treatment of MS lymphocytes with interferon resulted in only a slight increase in NK activity, while NK activity of normal individuals was markedly augmented by interferon. Leukopheresis of MS patients gave a rapid decrease in cytotoxic activity, which returned to pretreatment levels by 24 hrs. These results are consistent with the hypothesis of an immune deficit in multiple sclerosis.

Adult↗

PubMed1982

[Results of a comparative therapy study for inoperable lung cancer].

In a prospective randomized study 78 selected patients with bronchogenic cancer have been included, and five different treatment modalities have been compared (1. Biologic therapy; 2. Vitamin A + Cytoxan; 3. Vitamin A + Telecobalt irradiation; 4. Telecobalt irradiation; 5. Immunotherapy). No significant differences if survival times between the different groups have been observed. Nevertheless, significant differences of survival times were found between small cell and squamous cell carcinoma patients without respect to the therapy applied. The highest number of remissions was obtained by therapy 3, followed by 4 and 2. Consequences for further studies are discussed.

Adult↗

PubMed1982

[Ifosfamide versus ifosfamide + CCNU in the treatment of inoperable small cell carcinoma of the lung. A clinical study].

55 selected patients with inoperable small cell carcinoma of the lung have been induced in a randomized prospective trial in order to compare the efficacy of ifosfamide monotherapy with the combination of ifosfamid + CCNU. Initially a control group, treated with symptomatic therapy only, was also included but preliminary analysis revealing that results were unfavourable in comparison to those of the chemotherapy group; this treatment arm was omitted. 53 of 55 patients were evaluable. In group 1 (symptomatic therapy) results were better as to patients' quality of life, but no tumor remissions have been observed and survival times were significantly shorter (15 to 122 days; geometric mean 42.35 days). In group 2 (ifosfamide monotherapy) one total remission (lasting 15 months) and 2 partial remissions (lasting from 3 weeks to 4 months) have been achieved; in this group survival was 3 to 473 days (geometric mean 110.15 days). In group 3 (ifosfamide + CCNU) 7 partial remissions have been observed (3 weeks to 4 months), survival was 17 to 477 days (geometric mean 107.32 days). The combination of ifosfamide with CCNU did not reveal any advantage in comparison to ifosfamide monotherapy.

Adult↗

PubMed1982

[Chemo-immunotherapy in disseminated malignant testicular tumors].

Since 1978 we have treated 26 patients with testicular cancer in stage IV with the following chemotherapy regimen: Vinblastine 6 mg/m2 (day 1 and 2) and bleomycin 30 mg given over 24 hour period (day 1 to day 5). After two cycles this therapy was changed and patients received the combination adriamycin 60 mg/m2 (day 1) and cis-DDP 20 mg/m2 (day 1 to 5) for further two cycles. We achieved 69% (18 of 26 patients) complete remissions. Patients without response or no change received as second treatment modality vincristine 0,8 mg/m2 (day 1) and ifosfamide 1500 mg/m2 (day 1 to 5). Before each chemotherapy in an interval of two days 1 Unit (= 1 KE) of OK-432 (Streptococcus pyogenes) preparation, an immunomodulating agent, was given intravenously. In the therapyfree interval of chemotherapy 2 KE of OK-432 were applied. The maintenance therapy for 1 year consisted of vinblastine and trofosfamide and also OK 432. For the achievement of complete remissions 4 courses of chemotherapy seemed to be sufficient. The inclusion of OK 432 immunotherapy in an already established chemotherapy regimen seems to be qualified due to the reduction of chemotherapy induced side effects (myelosuppression, immunodeficiency) and the immunorestoration achieved before chemotherapy.

Adult↗

PubMed1982

Radioimmunometric demonstration of immunoglobulin G on cancer cells derived from malignant pleural effusions.

Well-preserved viable cancer cells, lymphocytes and mesothelial cells were prepared from various human malignant and non-malignant pleural effusions by a Ficoll-Hypaque discontinuous gradient. Using 125I-labelled protein A from Staphylococcus aureus as tracer, IgG was found on all cancer cells and also on apparently non-malignant mesothelial cells. Loss of cell surface IgG by overnight incubation, and fluctuation of surface IgG levels in the same patient occurred with cancer cells as well as with mesothelial cells. The IgG in vivo coat of cancer cells reflected the IgG levels of the sera rather than those of the pleural effusions. Binding of IgG from autologous and allogeneic sera and from supernatants of acid and mild overnight elution of cancer cells and mesothelial cells did not indicate a cancer-specific uptake of IgG. Various unspecific modes of IgG uptake by cancer cells are discussed including the possibility of a non-immune mechanism. Modification and loss of antigens by metastatic cells have also been considered.

Cell Membrane↗

PubMed1982

Plasmapheresis in patients with advanced malignant disease: a pilot study.

Plasmapheresis has been performed in 16 patients with advanced malignant disease (12 malignant melanoma, 2 breast cancer, 2 colon cancer). Up to 3,000 ml of plasma (range 1,650-3,000 ml) have been replaced by one single plasma exchange. Side effects observed in about 50% of the patients were mainly nausea and chills. Serum proteins including acute phase reactants were monitored before and 2, 4, and 7 days after plasma exchange. A transient change of these proteins was observed in the first days, but, later on, pretreatment values were always retained. Peripheral blood lymphocyte blastogenic response to mitogens was increased in 5 out of 9 patients 7 days after plasma exchange. In 7 out of 9 patients pretreatment serum was found inhibitory to autologous lymphocyte reactivity to mitogens. Furthermore, plasmapheresis was found to decrease significantly the blocking effect of patients' sera on normal donor lymphocyte reactivity. Plasmapheresis was found tolerable in all patients treated, but without any clinical efficacy. Further studies are warranted to establish the therapeutic value of plasma exchange in patients with advanced malignancies.

Blood Proteins↗

PubMed1982

Development of cytotoxic cells during in vitro cultures of pleural effusion lymphocytes from patients with lung cancer.

Culture-induced cytotoxic (CIC) activity developed in 7-day culture in the presence of fetal calf serum of pleural effusion lymphocytes from patients with lung cancer which initially showed markedly low or no natural killing (NK) activity against K562 cells. The development of CIC activity was proliferation-dependent. The CIC-mediating effector cells were removed by nylon-wool adherence, whereas the NK cells were enriched. Precursors for cytotoxic cells were not clarified. These results suggest that the precursors for cytotoxic cells are present in carcinomatous pleural effusions and able to develop cytotoxicity after 7-day culture in vitro.

Adult↗

PubMed1982

Autologous mixed lymphocyte reaction in the peripheral blood and pleural effusions of cancer patients.

T cells proliferate in response to autologous non-T cells in the autologous mixed lymphocyte reaction (AMLR). AMLR was impaired in the peripheral blood of patients with advanced lung cancer (4,159 +/- 3,878 delta cpm vs. 11,221 +/- 4,156 delta cpm for normal donors) but normal or even higher in their malignant pleural effusions (13,257 +/- 7,075 delta cpm vs. 10, 870 +/- 5,013 delta cpm for nonmalignant control effusions). Blood T cells also failed to respond to autologous effusion non-T cells, while effusion T cells strongly responded to autologous erythrocytes blood non-T cells. The presence of blood T cells did not inhibit effusion AMLR of the same patients. A subset of T cells that form rosettes with autologous erythrocytes if found to proliferate in AMLR. The number of autorosette-forming cells was lower in blood T cells of cancer patients than in blood T cells of normal donors and in effusion T cells of the patients. After enrichment of autorosette-forming cells, there was no difference in AMLR of normal blood and cancer blood and effusions. These results indicate that the loss of AMLR in the blood of cancer patients is due to a reduction of number of autoreactive T cells and not to a defect of autologous stimulator non-T cells.

Adult↗

PubMed1982

Generation of suppressor cells for natural killer activity in cancer patients after surgery.

Natural killer (NK) cell activity was examined in breast cancer patients before and after surgery, and the cells involved in the postoperative depression of cytotoxicity were characterized. NK activity against K562 target cells determined in 4-hour 51Cr release assay of blood lymphocytes from preoperative patients was comparable to that of normal donors. After surgery the patients showed a decrease in NK activity but not in number of large granular lymphocytes in the effector cell populations. When blood mononuclear cells from postoperative patients were depleted of monocytes by adherence to a serum-coated plastic dish and a Sephadex G10 column and then cultured for 24 hours, they showed an increase in NK activity. Furthermore, adherent blood cells of postoperative patients, but not of normal donors or preoperative patients, suppressed the lytic function of NK cells of normal individuals. Twenty-four-hour preculture of suppressor and effector cells was required for suppression of cytotoxicity. Neither postoperative sera nor culture supernatants of suppressor monocytes and effector cells suppressed NK activity. In contrast, the lymphoproliferative response to mitogen was not affected by surgery, and postoperative blood monocytes did not inhibit the mitogenic response of normal lymphocytes. The results suggest that the appearance of suppressor monocytes in the circulation could be one cause of depression of NK activity in postoperative cancer patients.

Adult↗

PubMed1981

[Human interferons -- features and chances (author's transl)].

Interferons are soluble cellular products secreted by vertebrate cells in response to a wide variety of inducers. They confer resistance against many different viruses, inhibit proliferation of normal and malignant cells, impede multiplication of intracellular parasites, enhance macrophage and granulocyte phagocytosis, augment natural killer cell activity, and show several other immunomodulatory functions. In viral infections, interferon controls the spread of viruses by inhibiting viral protein synthesis and/or nucleic acid replication and by activating cellular immune responses which effectively eliminate virus-infected cells. Immune interferon, produced in a cellular immune response as the result of an infection, tumour, or hypersensitivity reaction, governs the local immune response to the abrogation of that tumour or other injury by directly reducing cell multiplication and recruiting cytotoxic cells. Clinical trials have shown some effectiveness of interferon in the treatment of chronic viral infections as well as some possible antitumour effects. Because of the extreme scarcity of human interferon and the use of highly impure preparations, the results to date are not conclusive. Therapeutic effectiveness rather than prophylactic effects, has still to be proved by controlled clinical studies with purified interferon under economically feasible conditions.

Fibroblasts↗