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Biomedical subjects

E Weidmann

Publications and source records attributed to E Weidmann.

At least 73 records · Page 4Linked to original sources
PubMed1992

The T-cell receptor V beta gene usage in tumor-infiltrating lymphocytes and blood of patients with hepatocellular carcinoma.

To determine a possibly restricted T-cell receptor (TCR) repertoire in tumor-infiltrating lymphocytes (TIL) in response to tumor-associated antigens in patients with hepatocellular carcinoma (HCC), freshly isolated TIL (n = 5) and peripheral blood lymphocytes (PBL; n = 6; 3 paired with TIL) were studied for expression of TCR variable (V) beta regions. RNA purified from TIL or PBL was reverse-transcribed into complementary DNA. This complementary DNA was amplified by quantitative polymerase chain reaction with 22 primers specific for 20 TCR V beta gene families and a 3' constant (C) beta primer. As a reference for later quantitation, a fragment of TCR C alpha was coamplified with each V beta region. Using 32P-labeled 3' primers, the percentage of total V beta expression was calculated by measuring the cpm of each of the amplified products. In contrast to PBL of 6 control, healthy individuals, whose range of expression of each TCR V beta gene varied from 0 to 13%, the expression of some V beta genes in HCC TIL was as high as 33%, indicating a restricted TCR V beta usage in HCC TIL. When polymerase chain reaction-amplified complementary DNAs of the V beta 1 or V beta 3 genes obtained from two TIL preparations were cloned and sequenced, the same rearrangements were found in the majority of DNA clones. The particular V beta genes that were over- or underrepresented in TIL varied among the patients. In 3 of 6 PBL and 3 of 5 TIL, the V beta 3 gene was expressed with a relatively high frequency. The V beta 4 gene expression was consistently low in patients' TIL or PBL. In 3 paired PBL and TIL, V beta expression was similar. In 5 of 6 cases, HCC PBL had different TCR V beta frequencies from those seen in normal PBL. This analysis of TCR V beta usage in freshly isolated TIL and in PBL indicated that T-lymphocytes in patients with HCC might have restricted immunological reactivity and that V beta 3-restricted TIL might represent antitumor effector cells.

Amino Acid Sequence↗
PubMed1992

Receptors for interleukin 2 on human squamous cell carcinoma cell lines and tumor in situ.

Several human head and neck squamous carcinoma cell lines were found to bind 125I-labeled or fluorescein-labeled interleukin 2 (IL-2). This binding was inhibited by an excess of cold ligand, IL-2, and by anti-p55 and anti-p70 monoclonal antibodies to the alpha and beta chains, respectively, of the IL-2 receptor (IL-2R). A small number (300/cell) of high-affinity IL-2R (2 x 10(-12) M) and a larger number (> 13,000/cells) of intermediate-affinity IL-2R (3 x 10(-10) M) were present on these tumor cells. By affinity cross-linking, tumor cells were shown to bind 125I-IL-2 to a M(r) 66,000 and 55,000 doublet peptide. The alpha and beta chains of the IL-2R also were detected on the surface of cultured tumor cells using the relevant monoclonal antibodies and flow cytometry. Immunoperoxidase staining with anti-p70 monoclonal antibody confirmed the expression of IL-2R on squamous cell carcinomas of the head and neck in situ. The presence of transcripts for p55/IL-2R-alpha and p70/IL-2R-beta in PCI-1 cells was confirmed by the polymerase chain reaction followed by hybridization to the IL-2R-alpha complementary DNA probe or IL-2R-beta complementary DNA probe, respectively. Our observations demonstrate that intermediate-affinity and high-affinity IL-2Rs are expressed on some human squamous cell carcinomas of the head and neck and that the receptors are functional, because growth of these tumor cell lines can be directly inhibited by exogenously supplied IL-2. The presence of IL-2R on human solid tumors could be important to consider, in addition to immunomodulatory effects of IL-2, in developing optimal therapeutic strategies for the administration of IL-2 to patients with cancer.

Antibodies, Monoclonal↗
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

Characterization of human autotumor-reactive T-cell clones obtained from tumor-infiltrating lymphocytes in liver metastasis of gastric carcinoma.

Three autotumor-reactive T-cell clones have been established from tumor-infiltrating lymphocytes isolated from a metastatic lesion of human gastric carcinoma in the liver. The clones all were shown to be CD3+, CD8+, CD4-, CD16-, T-cell receptor alpha/beta +, and T-cell receptor gamma/delta-, and they have retained both their autotumor reactivity and the same phenotype for over a year in culture. Each clone had a different rearrangement of the T-cell receptor gamma chain genes as indicated by Southern blot analysis. Tested against a panel of 18 tumor cell targets, the clones preferentially lysed autologous tumor (AuTu) cells, but each clone also showed weak cytotoxicity against one allogeneic cholangiocarcinoma cell line. At the same time, each clone showed appreciable cytotoxicity against K562 targets. In blocking experiments, anti-CD3, anti-WT31, anti-CD8, or anti-HLA class I monoclonal antibodies blocked AuTu cytotoxicity but not cytotoxicity against K562. In contrast, allocytotoxicity against the cholangiocarcinoma was blocked only by anti-CD3 monoclonal antibody. All 10 subclones of one T-cell clone had high levels of AuTu cytotoxicity but variable levels of anti-K562 cytotoxic activity. Proliferation of the T-cell clones was significantly stimulated by the addition of irradiated autologous but not allogeneic tumor cells. Preincubation of cultured AuTu cells with tumor necrosis factor alpha or gamma-interferon (IFN-gamma), but not with IFN-alpha, increased their susceptibility to lysis by the T-cell clones; however, it increased resistance of AuTu to lysis by interleukin 2-activated natural killer cells. The expression of an adhesion molecule, intercellular adhesion molecule 1, on the surface of AuTu was also up-regulated by tumor necrosis factor alpha or IFN-gamma, but not by IFN-alpha. All three cytokines up-regulated HLA-class-I antigens on AuTu. Pretreatment of K562 targets or allogeneic cholangiocarcinoma cells with the same cytokines increased their resistance to lysis by the T-cell clones. Overall, the results indicate that these T-cell clones show specificity for AuTu but also independently recognize a limited number of allogeneic tumor targets and lyse K562 targets. The mechanisms involved in the recognition by the T-cell clones of autologous, allogeneic, and K562 tumor targets appeared to be distinct.

Antibodies, Monoclonal↗
PubMed1991

[Comprehension and evaluation of drug risks through spontaneous notification].

Risk/benefit analysis of drugs requires not only the reporting and documentation of adverse drug reactions in clinical trials but also a spontaneous reporting system for the detection of rare adverse reactions to drugs. A central aspect of any spontaneous reporting system is assessment of causality on the basis of detailed case histories. However, besides the qualitative description of adverse drug reactions, information about the incidence of such reactions has to be obtained as well so that their frequency, and thus the risk involved, can be established.

Drug-Related Side Effects and Adverse Reactions↗
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↗
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

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↗
PubMed1987

Impaired T- and B-cell functions in patients with Hodgkin's disease. Reduced mitogenic responsibility and Il-2 production is not caused by defective CD4+-cells.

The mitogenic response of T-cell subsets, the production of interleukin-1 (Il-1) and interleukin-2 (Il-2) and in vitro immunoglobulin production was investigated in patients with Hodgkin's disease (HD). The mitogenic response of mononuclear cells (MNC) and the OKT4+ and OKT8+ subsets was greatly reduced in advanced disease stages and could only partially be restored with exogeneous Il-2. In untreated patients with HD--except those with highly advanced disease--the OKT4+ lymphocytes showed normal response to phytohemagglutinin in contrast to the MNC suggesting inhibiting agents or cells within in the MNC. These findings corresponded to reduced Il-2 synthesis of MNC, whereas isolated OKT4+--cells produced normal or elevated amounts of Il-2. MNC or monocytes produced normal or even higher amounts of lipopolysaccharide-induced Il-1 than controls. The results do not confirm a defect in this component of the interleukin system in HD. The immunological impairment was not limited to the T-cell system but involved B-cell activation and differentiation as well. The pokeweed mitogen-induced IgM, IgG and IgG production was highly suppressed in untreated HD, whereas the MNC of previously treated patients produced subnormal amounts of immunoglobulin in vitro. It is not yet clear whether this defect is T-cell-mediated or primarily a B-cell deficiency.

Adult↗
PubMed1987

Virus safety of pasteurized factor VIII and factor IX concentrates: study in virgin patients.

In a long term surveillance study hemophilia A and B patients were treated with a Factor VIII HS and Factor IX HS concentrate respectively, both pasteurized by heating in solution: 10 hours at 60 degrees C. None of 31 virgin hemophiliacs treated with Factor VIII HS Behringwerke developed hepatitis B during a follow up between 6 to 60 months. One patient who received 379.280 IU Factor VIII by 977 applications showed a seroconversion after 961 days of treatment. Passive/active immunisation is suggested. 4 patients had moderate elevations of transaminases (less than 120 U/l) without clinical signs of liver disease. 2 patients suffered a non-icteric NA NB-hepatitis two months after synovectomy in the same hospital. 6 virgin hemophilia B patients who had been treated with Factor IX concentrate HS Behringwerke remained serologically negative and did not develop any symptoms indicative of a hepatic disease during a follow up between 11-29 months. The HTLV-III safety of Factor VIII HS and Factor IX HS Behringwerke is presently under investigation by determination of the corresponding antibody.

Adolescent↗
PubMed1987

Virus safety of a pasteurized antithrombin III concentrate. Preclinical and clinical data.

Blood derived products carry the risk of virus transmission, especially for the hepatitis B virus (HBV), non-A/non-B virus(es) (NANBV) and human immunodeficiency virus (HIV). The precautionary measures for guaranteeing the virus safety of the pasteurized antithrombin III concentrate Kybernin HS/P are described and the efficacy of these measures is demonstrated by in vitro studies and by chimpanzee trials. The inactivation rate is greater than or equal to 10(6.7) for HIV, greater than or equal to 10(6.7) for HBV, and greater than or equal to 10(5.3) for NANBV (Hutchinson Pool). Clinically, virus safety was demonstrated by long-term drug surveillance as well as by both a retrospective and prospective clinical trial. The 13 participants of the prospective study were checked clinically and biochemically according to the standards of the International Committee of Thrombosis and Hemostasis (ICTH). Within an observation period of 12 months, no seroconversion has been detected for HIV or HBV. Neither have any increases in the transaminases occurred which would indicate NANB hepatitis.

Alanine Transaminase↗
PubMed1986

Pasteurization as an efficient method to inactivate blood borne viruses in factor VIII concentrates.

Heat treatment at 60 degrees C for 10 h in solution (pasteurization) was introduced into the manufacturing process of factor VIII concentrate (Haemate P) in order to considerably reduce the risk of transmission of human pathogenic viruses to haemophiliacs. The results of experimental and clinical studies with regard to hepatitis B, non-A, non-B hepatitis, acquired immune deficiency syndrome (AIDS) and herpes virus infections are reviewed. From this data it is concluded that pasteurization of factor VIII results in a product which is safe with regard to these viral infections. Furthermore, it was shown that pasteurization does not form new antigenic determinants on the factor VIII molecule and compared with the native product does not alter the physiological properties of this protein in patients. In comparison to these advantageous properties of the pasteurized product a slight loss of coagulant activity seems to be acceptable. This loss of yield, however, does not influence the quality or the amount of factor VIII in the final container used for the therapy of haemophilia A patients.

Deltaretrovirus↗
PubMed1985

Fibrin glue safety: inactivation of potential viral contaminants by pasteurization of the human plasma components.

Fibrin glue has become an indispensable tool in salvaging operations of the parenchymatous organs of the abdomen, in vascular and ophthalmic plastic surgery as well as neurosurgery. Currently available glues contain clotting factors from human plasma and thus carry the potential risk of transmitting viral infections like hepatitis or acquired immunodeficiency syndrome (AIDS). Combined efforts in selection of plasma donations as well as pasteurization of the human plasma products allow the manufacturing of a product (Beriplast) with virtually no risk of transmission of viral infections as demonstrated by in vivo and in vitro experiments with a variety of human pathogenic viruses. No changes in activity or antigenicity of the clotting factors by the pasteurization procedure have been encountered.

Acquired Immunodeficiency Syndrome↗
PubMed1981

Vasopressin in the plasma of stroke-prone spontaneously hypertensive rats.

1. Plasma concentration of arginine vasopressin, plasma osmolality and packed cell volume were measured in stroke-prone spontaneously hypertensive rats (SHRSP) and in normotensive Wistar-Kyoto (WKY) rats at different ages. 2. In young and in adolescent SHRSP, at 6, 9 and 12 weeks of age, plasma concentration of vasopressin was diminished as compared with age-matched WKY rats (P less than 0.01), whereas, in 18-week-old rats, the difference was not significant (P greater than 0.05). In contrast, in 24-week-old rats, plasma vasopressin was elevated as compared with WKY rats of the same age (P less than 0.01). 3. In none of the age groups did plasma osmolality differ between the two strains of rats, but in all groups packed cell volume in SHRSP was higher than in WKY rats. 4. During a 48 h period of dehydration, plasma vasopressin concentrations increased similarly in SHRSP and in WKY rats of 6 and 12 weeks of age respectively. 5. It is concluded that vasopressin does not contribute to the development of high blood pressure in SHRSP rats. The reduced plasma concentration of vasopressin may account for the decreased plasma and blood volume and the slightly elevated plasma sodium concentration observed in young SHRSP rats.

Animals↗