Biomedical subjects

H Link

Publications and source records attributed to H Link.

At least 307 records · Page 17Linked to original sources

PubMed1994

Organ-specific autoantigens induce interferon-gamma and interleukin-4 mRNA expression in mononuclear cells in multiple sclerosis and myasthenia gravis.

T cells recognizing the myelin components myelin basic protein (MBP) and proteolipid protein (PLP) are increased in multiple sclerosis (MS), and there are elevated numbers of T cells recognizing the nicotinic acetylcholine receptor (AChR) in myasthenia gravis (MG). However, the cytokine repertoires in these diseases are largely unknown. We adopted in situ hybridization with radiolabeled complementary DNA oligonucleotide probes to enumerate mononuclear cells that expressed the T-helper type 1 (Th1) cell-related interferon-gamma (IFN-gamma) and Th2-associated interleukin-4 (IL-4) after short-term culture in the presence of autoantigen. High numbers of IFN-gamma and IL-4 mRNA-expressing cells in response to MBP and PLP were detected in patients with untreated MS, and to AChR in MG. The levels of IFN-gamma and IL-4 mRNA-positive cells in MS after culture in the presence of AChR, and in MG after culture in the presence of MBP or PLP, did not differ from those detected after culture without antigen. The CSF of MS patients contained four- to eightfold more myelin protein-reactive IFN-gamma and IL-4 expressing cells. The findings imply that MS and MG are associated with mixed Th1- and Th2-like cell responses directed to organ-specific target antigens.

Adult↗

PubMed1994

Influence of K+ channel openers on interferon-gamma dependent immune response in experimental allergic neuritis (EAN).

We examined the influence of the K+ channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-gamma secreting cells (IFN-gamma sc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10(-5)M-10(-6)M and pinacidil at concentrations of 10(-5)M-10(-7)M enhanced the proliferative response to both BPM and PHA. The number of IFN-gamma sc was suppressed by the K+ channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-gamma sc than of cultures with low numbers of BPM-reactive IFN-gamma sc. The applied K+ channel openers are primarily acting on ATP-sensitive K+ channels, which have not been found in T cells so far. The drugs may, therefore, exert non-selective effects on conventional voltage- and/or Ca(++)-dependent channels of T cells. A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects.

Animals↗

PubMed1994

Treatment of poor marrow graft function with allogeneic CD34+ cells immunoselected from G-CSF-mobilized peripheral blood progenitor cells of the marrow donor.

The treatment effect of immunoselected allogeneic CD34+ blood cells was evaluated in two patients with poor graft function following BMT without evidence for immune-mediated rejection. Patient A had no signs of hematopoietic recovery up to day +34 post-BMT and patient B had normal leukocyte counts only with G-CSF support and remained platelet transfusion-dependent for > 200 days post-BMT. PBPC from the HLA-identical sibling BM donors were mobilized with G-CSF (2 x 5 micrograms/kg sc daily) for 5 days. Aphereses were performed on days 4 and 5 of G-CSF administration. CD34+ cells were separated from the pooled PBPC concentrates by immunoadsorption with the anti-CD34 moAb 12.8 in a biotin-avidin system. Patient A received 0.4 x 10(6) CD34+ and 4.3 x 10(5) CD3+ cells/kg body weight and patient B 3.4 x 10(6) CD34+ and 1.4 x 10(5) CD3+ cells/kg body weight. The trilineage repopulation of BM and the rapid improvement of peripheral blood parameters correlated with CD34+ cell infusion. Patients' blood and BM cell analyses proved the donor origin. Patient A died from CMV pneumonitis and multiorgan failure 27 days after CD34+ cell infusion (day +61 post-BMT). Patient B is still stable and in remission 260 days after CD34+ cell infusion (day +478 post-BMT). Neither patient suffered further exacerbation of GVHD). Thus, immunoselected allogeneic CD34+ blood cells might be appropriate for treatment of post-BMT graft failure.

Adult↗

PubMed1994

Incidence of local CMV infection and acute intestinal GVHD in marrow transplant recipients with severe diarrhoea.

Intestinal biopsy samples derived from 22 consecutive patients with severe diarrhoea (> 1.5 1/day for 3 or more consecutive days) following allogeneic BMT were analysed for the local presence of cytomegalovirus (CMV) and histological and immunohistological alterations described as typical for acute graft-versus-host disease (GVHD). Seventeen patients showed extensive histopathological lesions typical for acute intestinal GVHD grade > I, 14 marked GVHD-related immunohistological alterations. In intestinal biopsies from 10 of these 22 patients CMV-DNA was detected using PCR- and in situ hybridisation techniques. In 7 of these 10 CMV-DNA positive samples CMV protein expression and in 5 cytomegalic cells were demonstrated. CMV could predominantly be shown in biopsies obtained from the ascending colon and/or the terminal ileum. All 10 patients with local CMV infection showed severe histopathological and immunohistological alterations described as typical for acute intestinal GVHD. Five of seven patients with a CMV-positive intestinal biopsy showed marked improvement of lower gastrointestinal tract disease on antiviral therapy. Five of seven patients lacking local presence of CMV but with severe histopathological lesions responded to therapy with high-dose steroids. Thus, PCR screening for CMV and histopathological analysis may help to treat lower intestinal disease in the marrow transplant recipient early and effectively.

Adolescent↗

PubMed1994

The role of granulocyte-macrophage colony-stimulating factor in the treatment of germ cell tumors. German Testicular Cancer Study Group.

Hematopoietic growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), may gain increasing importance in the treatment of patients with malignant germ cell tumors. For patients with far advanced testicular cancer, who only have a chance of long-term cure in the range of 40% to 50% by standard induction chemotherapy, the German Testicular Cancer Study Group has shown that the application of GM-CSF after PEI chemotherapy has allowed the increase of dose intensity of this three-drug regimen by a factor of 1.4. In 75 evaluable patients an overall survival rate of 79% after a median follow-up of 27 months was achieved. The dose-limiting toxicity of this stepwise dose escalation protocol of the PEI regimen was severe mucositis/enteritis (World Health Organization [WHO] degrees 3/degrees 4) in 33% of the patients and prolonged thrombocytopenia (< 20,000/microL for more than 10 days). In future trials, hematopoietic growth factors will be used in the treatment of far-advanced testicular cancer to generate peripheral blood stem cells (PBSC) that can be used to overcome both granulocytopenia and thrombocytopenia. This approach with the use of PBSC and hematopoietic growth factors will allow us to apply multiple cycles of up-front dose-intensified PEI chemotherapy in this unfavorable subgroup of patients. However, with the establishment of an optimal hematopoietic support in these studies, the value of dose-intensified chemotherapy in advanced testicular cancer will have to be tested against standard dose regimens in prospective randomized trials.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Cytomegalovirus interstitial pneumonia in autologous bone marrow transplant recipients. Infectious Disease Working Party of the European Group for Bone Marrow Transplantation.

CMV pneumonia is rare following ABMT. No information has been presented concerning risk factors or outcome of antiviral therapy. Information concerning CMV pneumonia after ABMT was collected from bone marrow transplant centers in Europe. Twenty-one patients who fulfilled the diagnostic criteria of CMV pneumonia were reported. Eighteen of these patients were reported from centers who also reported the total number of ABMT performed. The CMV pneumonia frequency among 2252 reported ABMT patients was 0.8%, and this varied from 0% to 8.6% between different centers. Survival for > 30 days from diagnosis of pneumonia was 43%. Three patients suffered relapses, which were fatal, giving a total survival of 28%. Patients treated with or without TBI had a survival of 18% and 50%, respectively. Among patients given ganciclovir or foscarnet with or without intravenous immune globulin, survival at 30 days was 50% and total survival 28%. There was no difference in survival with or without the addition of intravenous immune globulin. CMV pneumonia is an infrequent but serious complication of ABMT.

Adolescent↗

PubMed1993

Interleukin-2 secreting cells in multiple sclerosis and controls.

To evaluate systemic T cell activation and reactivity against putative autoantigens in multiple sclerosis (MS), numbers of interleukin-2 (IL-2) secreting cells were determined in peripheral blood of 32 patients with MS, 7 patients with acute aseptic meningitis (AM) and 12 patients with tension headache (TH). Numbers of IL-2 secreting cells were higher in MS patients compared to patients with AM + TH after stimulation with myelin proteolipid protein (PLP), myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG), but not after stimulation with myelin basic protein (MBP). In response to MAG, MOG and acetylcholine receptor (AChR) the frequencies of IL-2 secreting cells were higher in patients with MS than TH, while there were no differences between AM and TH to any of the tested antigens. Between patients with MS and AM there was no difference regarding frequency of IL-2 secreting cells in response to any of the tested antigens except MAG to which the response was higher in MS patients. Six of 10 MS patients had IL-2 secreting cells in response to all four myelin antigens (MBP + PLP + MAG + MOG) or to three antigens, while this broad reactivity was not found in any control patient. There was no correlation between numbers of IL-2 secreting cells in MS patients and clinical variables, including exacerbation versus remission, disability and duration of disease. The results suggest that the systemic T cell response in patients with MS is directed to several antigens.

Adult↗

PubMed1993

Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group.

We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) ("events" being defined as failure to achieve complete remission [CR], occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% +/- 7% and 50% +/- 9% at 12 months, respectively, in the ATRA and the chemotherapy group (P = .001). Kaplan-Meier estimate of relapse was 19% +/- 8% and 40% +/- 12% at 12 months (P = .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.

Adolescent↗

PubMed1993

Cord blood contains high numbers of autoimmune T cells recognizing multiple myelin proteins and acetylcholine receptor.

To analyze Ag-specific T cell autoimmunity in the newborn, umbilical cord blood cells of newborns were investigated by an immunospot assay for occurrence and numbers of cells secreting IFN-gamma after short-term culture in presence of myelin basic protein (MBP), proteolipid protein, myelin associated glycoprotein, nicotinic acetylcholine receptor and the synthetic MBP amino acid sequences 1-20, 63-88, and 110-128. These Ag were chosen because they represent putative targets for autoimmune attack in multiple sclerosis and myasthenia gravis. Surprisingly, numbers of T cells recognizing MBP, proteolipid protein, MBP peptides, and acetylcholine receptor were high in cord blood of newborns compared to peripheral blood of patients with neurologic diseases. No immunodominant T cell epitope could be discerned among the Ag included. The responses to purified protein derivate and PHA were lower among cord blood cells than peripheral blood cells of adults. Parallel enumeration of autoimmune T cells in cord blood and peripheral blood obtained from corresponding mothers at delivery, revealed that the high cell numbers in newborns were not a result of contamination from the mothers blood. The high numbers of T cells recognizing nervous system myelin proteins and acetylcholine receptor in cord blood could have importance for the mechanism and timing of tolerance induction, and also reflect excessive myelination and receptor maturation at birth.

Adult↗

PubMed1993

T cell reactivity to acetylcholine receptor in rats orally tolerized against experimental autoimmune myasthenia gravis.

Myasthenia gravis and its animal model experimental autoimmune myasthenia gravis (EAMG) represent T cell-dependent autoimmune diseases mediated by antibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction. Oral administration of Torpedo AChR to Lewis rats prior to immunization with the myasthenogenic Torpedo AChR and complete Freund's adjuvant results in the prevention of clinical EAMG, and the suppression of AChR-specific B cell responses. To examine the influence of oral tolerance to EAMG on AChR-reactive T cells, we determined and enumerated such cells in the popliteal, inguinal, and mesenteric lymph nodes, spleen, and thymus by a T cell immunospot assay that is based on the secretion of interferon-gamma (IFN-gamma) by antigen-reactive T cells. A diminution of such cells was detected in popliteal, inguinal, and mesenteric lymph nodes of rats orally tolerized to EAMG compared to unfed or vehicle-fed animals. We conclude that oral administration of AChR, in addition to preventing clinical signs of EAMG and suppressing AChR-specific B cell responses, also counteracts the development of AChR-reactive IFN-gamma-secreting cells in certain lymphoid organs.

Administration, Oral↗

PubMed1993

Effect of recombinant human erythropoietin after allogenic bone marrow transplantation.

The hematologic effects of recombinant human erythropoietin after allogeneic bone marrow transplantation (BMT) were studied. Nineteen patients received 150 U/kg/day of C127 mouse-cell-derived recombinant human erythropoietin (rHu EPO) as a daily continuous intravenous infusion until hematocrit exceeded 35%. These data were compared with a treatment-matched historical control group of 43 patients. RHu EPO-treated patients recovered erythropoiesis more rapidly and became independent from erythrocyte transfusions after a median of 17 days, which was 7 days earlier than the control patients.

Adolescent↗

PubMed1993

Autoreactive T and B cell responses to myelin antigens after diagnostic sural nerve biopsy.

To study whether nervous tissue trauma provokes myelin antigen autoreactive T and B cell responses in humans we examined consecutive blood samples from 7 patients with polyneuropathy undergoing diagnostic sural nerve biopsy and 8 control patients undergoing other types of minor surgery. The antigen-specific T cells were assessed by enumerating cells secreting interferon-gamma (IFN-gamma) in response to the myelin components P0, P2, myelin basic protein (MBP) and myelin associated glycoprotein (MAG), and to 4 selected MBP peptides. B cell mediated immunity was assessed by counting numbers of cells secreting antibodies directed against the myelin proteins. On day 7 after biopsy, there were 3-10-fold increased numbers of T and B cells reactive with P0, P2, MBP and MAG in blood of polyneuropathy patients compared to controls, while levels of cells recognizing purified protein derivate or responding to phytohemagglutinin (PHA) did not differ significantly. Comparison of prebiopsy levels on day 0 with post-biopsy levels on day 7 in the polyneuropathy patients revealed a significant increase in T cells recognizing P0, P2 and MAG, and in B cells secreting IgG antibodies against P0 and P2. On day 14 after nerve biopsy these differences were no longer seen. We suggest that in patients with polyneuropathy, sural nerve biopsy with the ensuing wallerian degeneration and myelin breakdown causes transiently increased levels of circulating myelin autoreactive T and B cells. It remains to be determined if this has a physiological role in nerve trauma responses and/or affects the clinicopathological course of the peripheral neuropathy.

Adolescent↗

PubMed1993

Cyclothialidine and its congeners: a new class of DNA gyrase inhibitors.

Cyclothialidine is a new, potent DNA gyrase inhibitor isolated from Streptomyces filipinensis. However, it exhibits hardly any growth-inhibitory activity against intact bacterial cells. To explore its potential with regard to the development of a new type of antibacterial, a flexible synthetic route was worked out (i) to investigate the structural requirements for DNA gyrase inhibition and (ii) to search for congeners exerting antibacterial activity. The structure of cyclothialidine was confirmed by total synthesis. Marked DNA gyrase inhibitory activity was found for a number of analogs, a common feature of them being the bicyclic 12-membered lactone bearing one phenolic hydroxy group. Congeners of cyclothialidine were found to exhibit a moderate, but broad-spectrum, in vitro activity against Gram-positive bacteria. Therefore, the DNA gyrase inhibitory principle contained in cyclothialidine can be considered as the basis for a new class of antibacterial agents.

Anti-Bacterial Agents↗

PubMed1993

Suppression of experimental autoimmune myasthenia gravis by oral administration of acetylcholine receptor.

Experimental autoimmune myasthenia gravis (EAMG), which to some extent represents an experimental counterpart of human myasthenia gravis, can be induced by inoculation of various animal species and strains with acetylcholine receptor (AChR). The oral administration of Torpedo AChR to Lewis rats prior to immunization with Torpedo AChR and complete Freund's adjuvant resulted in prevention or delay in the onset of EAMG. Levels of anti-Torpedo AChR antibodies in serum measured by radioimmunoassay were lower in orally tolerant compared to control animals. The model might have a relevance for studying the pathogenesis and immunotherapy of human myasthenia gravis.

Administration, Oral↗

PubMed1993

B cell autoimmunity to acetylcholine receptor and its subunits in Lewis rats over the course of experimental autoimmune myasthenia gravis.

Experimental autoimmune myasthenia gravis (EAMG) is induced by a single injection of acetylcholine receptor (AChR) with complete Freund's adjuvant and represents a useful animal model for studying the mechanisms by which autoimmune responses to AChR and its subunits are coupled to the development of human myasthenia gravis. Using an immunospot assay, we enumerated cells secreting IgG antibodies against Torpedo AChR and the alpha-, beta-, gamma- and delta-subunits of Torpedo AChR in lymph nodes, spleen and thymus from Lewis rats over the course of EAMG. Cells secreting IgG antibodies to AChR and to all four subunits were detected at higher numbers in the three immune organs in EAMG compared to controls. Numbers were highest in lymph nodes followed by spleen and thymus. Cells secreting IgG antibodies against native AChR were always higher than those against individual subunits. The immunogenicity between the four subunits did not differ, with the exception that the alpha-subunit induced a slightly higher B cell response in thymus and lymph nodes. The patterns of B cell responses were similar when analyzed over the course of EAMG from week 2 to week 5, and there was no restriction of the B cell repertoire early in EAMG. Anti-AChR and anti-subunit antibody-secreting cells were also detected in control animals immunized with adjuvant only, but at numbers which were much lower, and which were within the same level as numbers of cells secreting IgG antibodies to the control antigen myelin basic protein, probably reflecting naturally occurring autoimmune B cells.

Animals↗

PubMed1993

Oligoclonal IgG in cerebrospinal fluid detected by isoelectric focusing using PhastSystem.

Identification of oligoclonal immunoglobulin G (IgG) in cerebrospinal fluid (CSF) is one of the major laboratory signs in multiple sclerosis (MS). Oligoclonal IgG can also be seen in other immunostimulating central nervous system diseases, e.g. meningitis caused by Borrelia spirochetes. A convenient isoelectric focusing (IEF) method combined with polyethyleneglycol-enhanced (PEG) immunofixation and silverstaining using PhastSystem for detection of oligoclonal IgG bands in serum and unconcentrated spinal fluid was developed. Serum and cerebrospinal fluid samples earlier investigated using agarose IEF combined with immunoblotting and avidin-biotin amplified double-antibody peroxidase staining (= A-IEF) were blindly re-analysed using PhastGel IEF 3-9 modified with addition of Pharmalyte 8-10.5 followed by immunofixation and silver staining (= PhastIEF). PhastSystem IEF using PhastGel had the same capability to separate and visualize oligoclonal IgG bands as the conventional agarose IEF. However, PhastIEF was more convenient and less time-consuming than A-IEF. PhastIEF combined with immunofixation and silver staining using application of standardized amounts of IgG for both the serum and CSF samples (40-60 ng IgG/lane is fast, well-standardized and reproducible. The method is sensitive and uses only a minute volume of unconcentrated cerebrospinal fluid for the investigation of CSF IgG pattern.

Cost-Benefit Analysis↗

PubMed1993

Antigen processing: where tumor-specific T-cell responses begin.

It is well established that tumor-specific CD8+ T cells have the capacity to prevent and cure malignancies in animals under experimental conditions. This has raised expectations that it will prove possible to achieve similar successes with human cancers. CD8+ T cells recognize peptides of 8-10 residues derived from cytosolic proteins that are bound to the class I molecules of the major histocompatibility complex. To most effectively manipulate the T-cell response to tumor cells, it is essential to understand the means by which the peptide-class I complex is created in cells. An overview of this process is provided with an emphasis toward the recent findings made by our laboratory.

Animals↗

PubMed1993

Monitoring of relapse and remission in acute leukaemias by DNA-fingerprint analysis.

DNA-fingerprint (DNA-F) analysis was successfully performed with DNA from 22 adult patients with acute leukaemia, including 13 patients with acute myeloid leukaemia (AML) and nine patients with acute lymphoblastic leukaemia (ALL). The purpose of this study was to detect differences between the leukaemic phase (at diagnosis or relapse) and remission-phase DNA. We applied one simple repeat probe (GTG)5 and one minisatellite (M13) after DNA-digestion with different restriction endonucleases (HinfI and HaeIII) and agarose gel electrophoresis. In 7/13 patients with AML and 5/9 patients with ALL it was possible to detect loss of bands, additional bands or band shift with at least one of the probes. Together the probes M13 and (GTG)5 unveiled deviating fingerprint patterns in 54.6% of patients between leukaemic cells and remission-phase leucocytes. Allogeneic bone marrow transplantation was performed on six patients. In each case the DNA-F pattern of the donor was different from the relapse and the remission-phase pattern. We conclude from our studies that the probes M13 and (GTG)5 are useful in the detection of relapse and remission in acute leukaemias after chemotherapy and bone marrow transplantation.

Acute Disease↗