Search PubMed⌕ Search

Biomedical subjects

L Bergmann

Publications and source records attributed to L Bergmann.

At least 19 recordsLinked to original sources
PubMed1992

Cytotoxic action of IL-1 beta against pancreatic islets is mediated via nitric oxide formation and is inhibited by NG-monomethyl-L-arginine.

IL-1 beta has been previously shown to act as a cytotoxic agent in islets. Here we show by electron microscopy of alginate encapsulated islets, that islet cell lysis is induced by culturing islets for 24 or 48 h in the presence of IL-1 beta. The extent of lysis depends on the IL-1 beta concentration and is slightly enhanced by the addition of TNF-alpha. Cells can be protected from lysis by NG-monomethyl-L-arginine. Lysis is paralleled by an increase in nitrite concentration in culture supernatants of whole islets but not in supernatants of isolated endocrine cells. The results indicate that IL-1 beta toxicity occurs via inducing in non-endocrine islet cells the synthesis and release of nitric oxide, which has been shown earlier to be highly toxic for islet cells.

Animals↗
PubMed1992

Rapid cytokine release in cancer patients treated with interleukin-2.

Serum concentrations of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-6 (IL-6), interleukin-1 (IL-1) and interferon-alpha (IFN-alpha) were determined by commercially available enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) in cancer patients treated with recombinant IL-2 (rIL-2) either as 1-h infusion (3 or 5 x 10(6)/m2) or continuous intravenous infusion for 5 days (3 x 10(6)/m2/day). A significant increase of TNF-alpha and IL-6 serum levels was observed in each patient. One-hour infusion of IL-2 induced a very rapid secretion of TNF-alpha, IL-6 and IFN-gamma with considerably higher peak levels than during IL-2 continuous intravenous infusion. IFN-gamma was released into the blood of all patients receiving IL-2 1-h infusion, but only occasionally during or after IL-2 continuous intravenous infusion. Neither IFN-alpha nor IL-1 were detectable in the serum before, during, or following IL-2 treatment in all patients studied. The kinetics of IL-2 after 1-h infusion fitted to a two-compartment model, suggesting the synthesis of considerable amounts of endogenous IL-2. Following IL-2 1-h infusion, rising TNF-alpha serum levels preceded the increase of serum IFN-gamma or IL-6. The serum peak levels of IFN-gamma and IL-6 decreased rapidly with a half-life of 0.29 to 2.5 h. The concentration time profiles of TNF following 1-h infusion of IL-2 demonstrated a considerably longer half-life than that of intravenously administered recombinant TNF as done in other studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Renal Cell↗
PubMed1991

High release of tumor necrosis factor alpha, interferon gamma and interleukin-6 by adherent lymphokine-activated killer cells phenotypically derived from T cells.

Adherent lymphokine-activated killer cells (A-LAK) are highly potent cytotoxic cells, which are shown to be derived not only from natural killer (NK)/K cells but phenotypically also from T cells. The generation and phenotypical and functional characterisation of these T-cell-derived A-LAK are described. In contrast to non-adherent cells (NA-LAK) and unseparated LAK (UN-LAK), these mostly CD3+ CD56+ CD8+ cells display a high degree of expansion following initial interleukin-2 (rIL-2) activation and further culturing in autologous conditioned medium. A comparison of cytotoxic activities of cultured cells reveals a significantly higher oncolytic ability of A-LAK cells against both K562 and Daudi cells than that of cultured controls of NA-LAK and UN-LAK. In addition, A-LAK are characterised by a marked endogenous cytokine release of interferon gamma, tumour necrosis factor alpha and IL-6 as well as by their shedding of p55 IL-2 receptor after exposure to IL-2. The results demonstrate A-LAK to be the lymphocyte subpopulation with the most cytotoxic activity and endogenous cytokine release after exposure to IL-2. The improvement of techniques for long-term cultures may be of interest for future therapeutic approaches.

Cell Adhesion↗
PubMed1991

Cytotoxic activity and phenotypic characteristics of lymphocyte subsets after therapy of cancer patients with interleukin-2.

After a 5-day period of continuous intravenous infusion of recombinant interleukin 2 (rIL-2) in seven patients with malignant melanoma or gastric or pancreatic cancer, different lymphocyte subsets were separated from patients' blood and tested ex vivo for cytotoxic activity against various tumour cell lines. Lytic activity was mediated by CD3+CD56+, CD3-CD56+, CD3-CD2+ and CD8+CD56+ lymphocytes. No cytotoxic activity could be observed within the CD3+CD56-, CD3+CD2+ or CD4+ T cell subsets. To characterize CD56+ cytotoxic cells further, the expression of other antigens on this population was analysed before and after IL-2 therapy. CD3, CD4, CD16 and CD57 antigens were weakly expressed, and the IL-2 receptor (CD25) was not detectable on these cells either before and after treatment with IL-2. In contrast, increased expression of CD2. CD8 and HLA-DR antigens occurred following therapy. The divergence of CD3 and CD8 antigen expression after IL-2 therapy was caused by an increase in CD3-CD8+ cells, detectable as a low-density CD8+ subset. This study shows that cytotoxic activity of in vivo IL-2-activated killer cells is predominantly, but not exclusively, mediated by CD3-CD56+ lymphocytes, partially coexpressing the CD8 antigen and lacking the expression of CD16 antigens.

Antigens, CD↗
PubMed1991

Cisplatin, etoposide, ifosfamide, vincristine and bleomycin combination chemotherapy for far advanced testicular carcinoma.

Forty-eight patients with advanced testicular cancer, defined as abdominal mass greater than 10 cm, mediastinal mass greater than 5 cm, more than 20 lung metastases, or visceral organ involvement were treated with an intensive, alternating five-drug regimen consisting of cisplatin 50 mg/m2 d 1-3, etoposide 170 mg/m2 d 1-3, ifosfamide 5 g/m2 d 15, vincristine 2 mg weekly, bleomycin 15 mg/m2 weekly, q d 28. Thirty-four (71%) of the patients attained tumor-free status. This was achieved by chemotherapy alone in 14 patients and by surgical resection of residual disease in the remaining 20 patients (histology of resected tissue: necrosis 12, mature teratoma 7, viable carcinoma 1). Patients with pure seminoma responded better than patients with nonseminoma (CR 100% vs. 67%, respectively). In a univariate analysis only the value of HCG (less than vs greater than 10,000 U/L) and the number of involved organ sites (less than or equal to 2 vs greater than to 2) had significant influence on the response rate. After a minimum follow-up of 24 months 3 patients (9%) have relapsed. The survival rate is 76% after 36 months, with 61% remaining disease-free. Though this intensive regimen might bestow some of the therapeutic advantages of standard three-drug protocols in far advanced testicular cancer, the results are still less than optimal and warrant the exploration of new therapeutic strategies.

Adolescent↗
PubMed1991

[Pearl oyster dust as the cause of exogenous allergic alveolitis].

Many different inhalative substances may cause allergic alveolitis (hypersensitivity pneumonitis). We report on a worker who developed lung fibrosis due to the sensitization to pearl oyster shell dust. High concentrations of IgG antibodies to proteins (conchagens) of the shell which appear to represent the relevant antigens were found in the patient's serum.

Aged↗
PubMed1991

[Damage to the corneal endothelium caused by radial keratotomy].

In our experimental study on 53 rabbits we compared the amount of corneal endothelial damage caused by radial keratotomy (RK) referred to (1) the number of incisions (4, 8, or 16), (2) the postoperative interval (0 h, 48 h) and (3) the direction of the incision [centripetal (cp), centrifugal (cf)]. The endothelial damage was quantified by means of the Janus green photometry technique. Morphological changes were evaluated by scanning electron microscopy (SEM). Depending on the group examined, we found endothelial damage extending over 3-7% of an analysed surface of 64 mm2. One perforation caused endothelial damage of up to 17% of the surface examined. Increasing the number of incisions from 4 to 8 or 16 resulted in a statistically significant increase in the amount of endothelial damage (4.2%, 5.1%, 5.8%; P less than 0.05). At 0 h it was significantly higher than after 48 h (5.5%, 4.6%; P less than 0.05). The direction of the incision had no statistically significant influence in our study (zp: 5.2%, zf: 4.9%). The morphological changes in the rabbit corneal endothelium examined directly after the RK procedure were ruptures in the cell membranes, loss of cells, and posterior corneal protrusions beneath the incisions. After 48 h, we found fewer damaged cells and no denuded Descemet's membranes, but larger polymorphy of the cells and a numerical increase in the microvilli of the cells surrounding the damaged cells. Our results support the crucial argument against RK: the alteration and destabilization of healthy corneal tissue up to the endothelium.

Animals↗
PubMed1990

Biotinyl analogues of vasopressin as biologically active probes for vasopressin receptor expression in cultured cells.

Biotinyl analogues of [Arg8]vasopressin were synthesized with the biotinyl moiety at position 4. This involved the substitution of 2, 4-diaminobutyric acid (Dab) for Gln4 in [1-deamino-Arg8]vasopressin to give the parent peptide des-[Dab4,Arg8]vasopressin. Two biotinyl analogues with different spacers between the side chain of Dab4 and the biotinyl residue were then prepared and characterized in detail. The analogues retained high binding affinities for the V2-receptor in both bovine kidney membranes and LLC-PK1 renal epithelial cells and for the V1-receptor in rat liver membranes. Both analogues were as potent as [Arg8] vasopressin in stimulating the cAMP-dependent protein kinase and the production of urokinase-type plasminogen activator in LLC-PK1 cells, with concentration dependence consistent with receptor binding affinities. Avidin or streptavidin did not appear to reduce receptor binding or biological activity of the biotinyl analogues. The use of the biotinylated vasopressin analogue des-[Dab-(biotinylamido)hexanoyl4, Arg8]vasopressin together with fluorescein-labeled streptavidin as a fluorescent probe for the V2-receptor in LLC-PK1 cells demonstrated the following: 1) Specific binding of the biotinyl analogue shown by quantitative single-cell fluorescence measurements using the technique of fluorescence microphotolysis; 2) the V2-receptor visualized by fluorescence microscopy; and 3) the expression of the V2-receptor detected by flow cytometry.

Amino Acid Sequence↗
PubMed1990

Quantitative and functional restorations and alterations of peripheral lymphocytes in patients with autologous spleen implantation.

To reduce the risk of severe infections in splenectomized patients, new methods for splenic preservation or heterotopic autologous spleen implantation have been established. In the latter case, the immunological and functional benefits are still under discussion. In this study we compared immunological parameters in 16 splenectomized patients with and without heterotopic autologous spleen implantation with a nonsplenectomized control group. The total lymphocyte counts--T-cells, CD4+ -, as well as CD8+ - lymphocytes, CD16+ - and B-cells--were highly elevated in both groups, whereby the B-cells were relatively and absolutely higher in the implanted group than in the nonimplanted group. Splenectomized patients had a significantly reduced serum IgM level. The serum IgM of patients with splenic autotransplantation was not significantly lower than that of the controls. In contrast to the impaired in vitro immunoglobulin synthesis in the splenectomized group, the autotransplanted patients showed a normal PWM-induced IgG and IgM synthesis and an increased IgA production compared with the controls. The latter results support the findings of elevated serum IgA levels in this group. The mitogenic-induced proliferation with PHA, ConA, PWM, and OKT3 was not clearly different within the tested groups. The results may indicate a benefit of autologous spleen implantation in regard to the humoral immune response.

Adolescent↗
PubMed1990

Intrinsic B lymphocyte defect in untreated patients with Hodgkin's disease.

In vivo and in vitro humoral and cell-mediated immunological defects have been described in untreated patients with Hodgkin's disease (HD). The cellular basis of the recently described in vitro reduction of mitogen-induced immunoglobulin synthesis has not been elucidated so far. In this study, we attempted to dissect T and B lymphocyte function in untreated HD patients. Mitogen-induced in vitro immunoglobulin synthesis was assessed in the presence of pokeweed mitogen, the mitogenic anti-CD3 monoclonal antibody OKT3 and the relatively T-cell-independent B cell mitogen Nocardia opaca delipidated mitogen (NDCM). Mitogen-induced Ig synthesis by HD peripheral blood mononuclear cells was significantly reduced compared to that in control peripheral blood mononuclear cells. In coculture assays, T cells of HD patients exerted an adequate helper function to control B cells. However, normal donor T cells did not restore Ig synthesis by B cells of HD patients. Finally, B cells of HD patients were unresponsive to NDCM, which is able to induce Ig synthesis in control B cells even in the absence of T cells. These data provide evidence for an intrinsic functional B lymphocyte defect in HD patients, and suggest that increased activation of suppressor HD T lymphocytes may not play a significant role in the suppression of in vitro Ig synthesis.

Antibody Formation↗
PubMed1990

Interleukin-2 in combination with interferon-alpha in disseminated malignant melanoma and advanced renal cell carcinoma. A phase I/II study.

In vitro, the combination of interleukin-2 (Il-2) with interferon-alpha (IFN-alpha) seems to act synergistically on the generation of lymphokine activated killer (LAK) cells. Due to this fact two clinical trials with the combination of Il-2 and IFN-alpha were initiated in malignant melanoma (MM) and renal cell cancer (RCC). Patients with disseminated MM were treated by a sequential application of 10 x 10(6) U/m2 rIFN-alpha 2b s.c. on days 1-7 followed by continuous intravenous infusion of 3 x 10(6) U/m2 rIl-2 on days 8-13 and 15-20. After a pause of 4 weeks the cycle was repeated. In advanced or disseminated RCC, the patients were treated with a daily alternating scheme of 10 x 10(6) U/m2 rIFN-alpha and rIl-2 as 1 h infusion 1 x /day for 14 days. The rIl-2 escalates intra- and interindividually beginning with a dose of 3 x 10(6) U/m2. The cycles were repeated after a pause of 3 and 4 weeks, respectively. The preliminary results show that the schedules are practicable and that the toxicity of the combination of rIl-2 and IFN-alpha does not accumulate. Within the MM group 3/11 evaluable patients achieved partial remission and 2/11 stable disease. In the RCC-group 2/5 evaluable patients achieved partial remission and 2/5 had stable disease so far.

Carcinoma, Renal Cell↗
PubMed1990

The clinical significance of interleukin-2.

The induction and activation of autologous cytotoxic cells (lymphokine activated killer cells = LAK) by interleukin-2 (Il-2) is an interesting new approach in cancer treatment. So far, Il-2 alone or in combination with the transfer of in vitro activated LAK (adoptive immunotherapy = AI) was shown to be effective predominantly in renal cell cancer and malignant melanoma with a response rate of 20-35%. The results in colorectal tumors are disappointing. Clinical experiences with Il-2 in other tumor entities are limited and/or mostly lack sufficient responses. To improve therapeutic results and to reduce the serious side effects, present trials focus on combinations of Il-2 with other cytokines, predominantly interferon-alpha (IFN-alpha), or chemotherapy. So far, the combination of Il-2 + IFN-alpha seems to be at least as effective as Il-2 + AI in renal cell cancer. Combinations of chemotherapy and Il-2, especially in gastrointestinal tumors, have not been shown to exceed the moderate results of chemotherapy alone so far. Trials with highly activated or specific cytotoxic cells as tumor-infiltrating lymphocytes (TILs) or adherent-LAK-cells are still more experimental. The value of IL-2 for elimination of minimal residual disease in acute leukemias after autologous bone marrow transplantation or as consolidation of complete response will have to be defined. The present paper reviews clinical studies with Il-2 in malignancies and its significance for therapeutic approaches.

Combined Modality Therapy↗
PubMed1990

Influence of various cytokines on the induction of lymphokine-activated killer cells.

The clinical use of interleukin-2 (IL-2) for generation and activation of cytotoxic lymphocytes lymphokine-activated killer cells (LAK) has principally demonstrated that tumors can be restricted by modulation of the immune system. However, innovative approaches are required to improve the therapeutic results. In this connection, combinations of IL-2 with other cytokines may be of interest to increase the numbers and cytotoxic activity of LAK. On the other hand, IL-2 itself mediates immune reactions and secretion of various cytokines. Therefore, we investigated the effect of interferon-alpha (IFN-alpha), IFN-gamma and tumor necrosis factor (TNF-alpha) on the induction of LAK activity by IL-2, and the induction of IFN-gamma and TNF-alpha by IL-2. LAK activity could not be enhanced by IFN-gamma and TNF-alpha, but was enhanced by IFN-alpha. This may in part be due to the fact that IL-2 itself induces high amounts of TNF-alpha and IFN-gamma. Besides the effect of IFN-alpha on LAK activity, an increased susceptibility of tumor cells for LAK in vitro could be achieved by preincubation of tumor cells with IFN-alpha. This mechanism seems not to be related to an increased expression of MHC class I and II antigens.

Cells, Cultured↗
PubMed1989

Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes--a phase I/II trial.

In a phase I/II study, 11 patients with myelodysplastic syndromes (MDS) and severe transfusion-dependent cytopenia were treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to investigate the effects of rhGM-CSF on normal hematopoiesis and leukemic cells. The treatment schedule included dose escalation from 15 micrograms/m2 to 150 micrograms/m2 administered by continuous intravenous (IV) infusion for seven to 14 days and was repeated after a two-week treatment-free interval. The blood leukocyte counts increased dose dependently by 130% to 1,800% in ten patients; a rise of monocytes and eosinophils occurred in seven and six patients, respectively. No sustained increase in reticulocytes or platelets was observed. Lymphocyte counts increased in all patients affecting both T-helper and T-suppressor cells; however, the lymphocytes were not activated as analyzed by the expression of the interleukin-2 receptor. In four of the patients, all with greater than 14% blast cells in the bone marrow, the percentage of bone marrow blast cells increased during treatment with rhGM-CSF. Cytogenetic data indicated induction of both proliferation and differentiation of the leukemic clones by rhGM-CSF. Toxic side effects were minor with slight fever, phlebitis at the infusion site, and bone pain in the minority of patients. In conclusion, rhGM-CSF effectively stimulates hematopoiesis in vivo in patients with myelodysplastic syndromes. However, as the leukemic cell population can be stimulated in patients with a higher initial blast cell count, the combination of rhGM-CSF with other differentiation-inducing or cytotoxic agents has to be considered.

Aged↗
PubMed1989

Malignant melanoma--prognosis and actual treatment strategies with chemotherapy and biological response modifiers.

The prognosis of malignant melanoma (MM) depends on the level of invasion, vertical tumour size, location of the primary, clinical stage, and sex. Whereas MMs are potentially curable in the early stage of disease, the therapeutic possibilities are very limited in advanced and disseminated MM. Most chemotherapeutic agents lack sufficient activity in MM especially with regard to survival. Dacarbazine (DTIC) is the most effective drug in MM with response rates of 20-25% followed by other drugs such as melphalan with 15-20%, hydroxyurea and platin derivates. Multidrug regimens were not shown to be more effective than DTIC alone. Radiotherapy may be relevant in local treatment of metastases. With regard to the poor prognosis and limited therapeutic approaches in advanced and disseminated MM, new strategies are required. In this context immunotherapeutic strategies with biological response modifiers are of interest for adjuvant or palliative approaches. Earlier trials with Bacillus Calmette-Guerin (BCG) +/- DTIC as adjuvant or palliative treatment revealed no effect of BCG on the prognosis. Alpha-interferon (alpha-IFN) was shown to induce remissions in about 15% and gamma-IFN in about 10% of patients. A very interesting new approach is the induction and/or activation of autologous cytotoxic cells by systemic administration of recombinant interleukin-2 (rIL-2) with response rates of 20-25% and the in vivo propagation and transfer of so-called tumour infiltrating lymphocytes. Further trials combining rIL-2 with other cytokines, chemotherapy, tumour vaccination or monoclonals against melanoma cells are required.

Humans↗