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Biomedical subjects

H Link

Publications and source records attributed to H Link.

At least 19 recordsLinked to original sources
PubMed1992

A controlled trial of recombinant human granulocyte-macrophage colony-stimulating factor after total body irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for acute lymphoblastic leukemia or malignant lymphoma.

Infections during granulocytopenia are major complications of autologous bone marrow transplantation (ABMT). Since recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) has proved to accelerate bone marrow recovery after cytostatic chemotherapy, we studied its effects on hematopoietic regeneration and on infectious complications after total body irradiation (TBI) and high-dose chemotherapy followed by ABMT. Eighty-one patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) or with non-Hodgkin's lymphoma (NHL) in CR or partial remission were randomized in a double-blind, placebo-controlled trial. They received either rhuGM-CSF 250 micrograms/m2 (Escherichia coli-derived) daily by continuous infusion after ABMT, or placebo. Treatment was continued until the neutrophil counts reached greater than 500/microL for 1 week. The maximum treatment duration was 30 days. Thirty-nine patients in the rhuGM-CSF group and 40 patients in the placebo group were evaluable. The median time needed to reach a neutrophil count of 500/microL was 15 days with rhuGM-CSF and 28 days with placebo (P = .0001). Bacterial infections occurred in 14 (35.9%) of the patients with rhuGM-CSF and in 25 (62.5%) of the patients given the placebo (P = .024). Nine of the 14 bacterial infections in the rhuGM-CSF group and 20 of the 25 infections in the placebo group were diagnosed within the first 10 days after ABMT. Capillary leakage and a reversible fluid retention were seen in five of the rhuGM-CSF-treated patients. Patients treated with rhuGM-CSF had lower serum protein and albumin levels than patients in the placebo group. There was no statistically relevant difference in overall survival between the two groups (P = .47). Relapse occurred in 14 (34%) patients with rhuGM-CSF and in 18 (45%) patients with placebo. We conclude that continuous infusion of rhuGM-CSF after ABMT accelerates the regeneration of granulocytes and reduces the number of bacterial infections.

Adult↗
PubMed1992

CD16- CD56+ natural killer cells after bone marrow transplantation.

Natural killer (NK) cells are phenotypically defined as lymphocytes expressing the antigens CD56 and mostly CD16 (Fc gamma RIII), but lacking CD3. A small CD3- CD16- CD56+ NK cell subset has been described in normal individuals representing less than 2% of peripheral blood lymphocytes. We analyzed here 70 patients for their reconstitution of the immune system during follow-up after autologous or allogeneic bone marrow transplantation. In 35% of these patients, two different NK cell subsets, namely CD56+dim and CD56+bright cells, were observed. The mean duration of these two subsets after transplant was 4 months. Sixty-five percent of the patients exhibited an increased number of NK cells, but only the typical CD16+ CD56+dim population. The CD56+bright subpopulation represented a particular CD3- CD16- NK subset, with posttransplant frequencies up to 70% of all NK cells and 40% of peripheral blood lymphocytes, respectively. In contrast to normal CD56+dim NK cells, CD56+bright cells coexpressed the activation antigens p75 beta-chain of interleukin-2 receptor (IL-2R), CD2R, and CD26, but were negative for CD16. NK and antibody-dependent cellular cytotoxicity activity of CD56+bright cells was low compared with CD56+dim NK cells. But using IL-2 and interferon gamma, their cytotoxicity could be enhanced even more than in CD56+dim lymphocytes. These different subsets may reflect distinct activation or differentiation steps of NK cells during reconstitution of the immune system. Their differential response to IL-2 may be of functional importance for posttransplant cytokine therapy.

Adult↗
PubMed1992

Increased numbers of T cells recognizing multiple myelin basic protein epitopes in multiple sclerosis.

Myelin basic protein (MBP)-autoreactive T cells have a crucial pathogenetic role in experimental allergic encephalomyelitis (EAE) and certain MBP epitopes may be immunodominantly recognized. The heterogeneity and quantity of the T cell response to different epitopes of MBP in multiple sclerosis (MS) and non-MS controls is not so clearly defined. We now study T cell reactivity to six different peptides of MBP in MS compared to controls in short-term cultures of blood mononuclear cells by measuring numbers of T cells that secrete interferon-gamma in response to antigen. In comparison with controls, MS patients showed dramatically increased numbers of MBP peptide-reactive T cells with mean values varying between 10.4 and 22.5 per 10(5) blood mononuclear cells. Among those MBP peptides examined (amino acid 1-20, 63-88, 89-101, 96-118, 110-128 and 148-165), no single peptide is preferentially recognized. Neither is any preferential response apparent after subdivision of the MS patients according to their HLA-DR genotype. Our findings suggest that a quantitative increase of a broad repertoire of myelin-autoreactive T cells with capacity to secrete IFN-gamma can be important for the pathogenesis of MS.

Adult↗
PubMed1992

T cell responses to human recombinant acetylcholine receptor-alpha subunit in myasthenia gravis and controls.

Antibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction are detectable in most patients with myasthenia gravis (MG) and assumed to participate in the destruction of the AChR, thereby, causing the characteristics signs and symptoms of the disease. The extent and importance of T cell responses to AChR and its subunits in MG are still unsettled. We have now examined T cell reactivities using human recombinant AChR-alpha subunit as antigen. Upon recognition of appropriate antigen in an MHC-class II-restricted fashion, memory T cells secrete interferon-gamma (IFN-gamma). Adopting this principle in an immunospot assay we found that 73% of MG patients had recombinant human AChR-alpha subunit-reactive T cells at a median value of 1 per 56,000 blood mononuclear cells, while only 27% of the MG patients responded to the alpha subunit in a conventional lymphocyte proliferation assay. This compares with even lower numbers of AChR-reactive T cells and 14% positivity in the proliferation assay among control subjects. The T cell responses to the control antigens purified protein derivative and myelin basic protein did not differ between MG and controls, underlining the specificity of an augmented T cell reactivity to AChR-alpha subunit in MG. Alpha Subunit-specific T cell lines and clones propagated from patients with MG and healthy controls yielded a high proportion of alpha subunit-reactive T cells in the IFN-gamma immunospot assay. Their appearance was inhibited by the addition of monoclonal anti-MHC class II antibodies, demonstrating that an MHC-restricted T cell response was measured. Our data underline that the AChR-alpha subunit is a major T cell autoantigen in MG.

Adolescent↗
PubMed1992

Detection of cytomegalovirus-infected cells by flow cytometry and fluorescence in suspension hybridisation (FLASH) using DNA probes labeled with biotin by polymerase chain reaction.

A biotin-labeled DNA probe specific for the immediate early gene of the cytomegalovirus (CMV) strain AD 169 was generated with the polymerase chain reaction. Nucleic acid hybridisation was carried out with CMV-infected T-lymphoblastoid cells (MOLT-4) after 4 hr to 6 days of culture. Biotin molecules were made visible with streptavidin coupled with fluorescein. The fluorescence signal of the hybridised probe was measured by flow cytometry in the cell suspension. The number of CMV-positive cells was 7% at 4 hr, 8% after 28 hr, 18% after 2 days, 26% after 3 days, 91% after 4 days, 97% after 5 days, and 98% after 6 days. The first detection of CMV antigen (pp65) was possible with immunoenzymatic labeling by day 4, whereas CMV-DNA was detected by PCR after 4 hr. CMV-specific RNA could be detected in a similar way. The analysis of mononuclear peripheral blood leukocytes in a patient with active CMV infection showed 14.7% CMV DNA-positive cells at day 1 and 7% at day 8, as compared to 0.9% and 0.0% cells which were positive for CMV antigen (pp65) by immunoenzymatic labeling at day 1 and day 8, respectively. We conclude that flow cytometry and fluorescence in suspension hybridisation (FLASH) offers a new tool for analysing exactly and quantifying large numbers of cells for specific DNA or RNA and may be useful for other laboratory and clinical applications.

Antigens, Viral↗
PubMed1992

Prednimustine and mitoxantrone (PmM) in patients with low-grade malignant non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and prolymphocytic leukemia (PLL).

Thirty-five patients with a mean age of 60.6 years (44-78 years, 22 male, 13 female) with advanced low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or prolymphocytic leukemia (PLL) were treated every 4 weeks with prednimustine 100 mg/m2 p.o. d 1-d 5 and mitoxantrone 8 mg/m2 i.v. d 1 and d 2. Seven patients had CLL, one lymphocytic NHL, two PLL, 13 immunocytoma, nine centroblastic/centrocytic NHL, and three centrocytic NHL. Twenty-five patients were pretreated. The subjective toxicity of the treatment was mild, with no WHO grade-3 alopecia, polyneuropathy, cardiotoxicity, mucositis, nausea, or vomiting. Hematologic side effects with WHO grade-4 granulopenia and thrombopenia were experienced by 26% and 23% of the patients, respectively. The overall response rate (CR+PR) was 72% for lymphoma patients and 37% for CLL patients, with a median remission duration of 14.6 months. The maximum response was achieved after a median of two treatment courses. Prednimustine with mitoxantrone is a subjectively well tolerated treatment for low-grade malignant NHL, to be further evaluated in phase-III studies. The regimen may shorten the duration of treatment, saving time-consuming out-patient visits and costs.

Adult↗
PubMed1992

Myasthenia gravis: T and B cell reactivities to the beta-bungarotoxin binding protein presynaptic membrane receptor.

Antibodies against acetylcholine receptor (AChR) can be detected in most patients with myasthenia gravis (MG) and are considered to be involved in the immunopathogenesis of this disease. AChR are isolated from crude receptor preparations by binding to alpha-bungarotoxin (alpha-BuTx). Patients with MG have also antibodies against a second protein tentatively named presynaptic membrane receptor (PsmR), which has been isolated from crude receptor utilizing beta-bungarotoxin (beta-BuTx). PsmR could represent another antigen besides AChR relevant for the development of MG. We have now evaluated the T cell reactivity to PsmR in MG and controls by analysing the frequencies of cells which in response to PsmR in short-term cultures secreted interferon-gamma (IFN-gamma). The B cell response to PsmR was analysed in parallel by counting cells secreting anti-PsmR antibodies. Most patients with MG had PsmR reactive T cell in blood with a median number of about 1 per 44,000 mononuclear cells. Cells secreting anti-PsmR antibodies belonging to the IgG and IgA isotypes, less frequently of the IgM isotype were detected in most MG patients. A positive correlation was found between T cells reactive with PsmR and anti-PsmR IgG antibody secreting cells. PsmR reactive T and B cells were also detected in control patients, but at much lower numbers. Our results indicate that MG is accompanied by T as well as B cell responses to PsmR, in addition to the previously recognized responses to AChR. It remains to be shown whether these PsmR reactivities are of pathogenetic importance in MG.

Adult↗
PubMed1992

Increased systemic B- and T-lymphocyte responses in hereditary motor and sensory neuropathy (HMSN I).

Immune mechanisms of possible importance for the development and maintenance of peripheral nerve myelin breakdown in HMSN I were analysed by measuring B- and T-cell activation in blood, bone marrow and cerebrospinal fluid. Patients with polyneuropathies of other etiologies served as one control group and patients with tension headache as another. Flow cytometry of blood and bone marrow mononuclear cells revealed that an increased number of CD3+, CD4+ and CD4- CD8- T-cells expressed a late stage activation marker (Ta1). Analysis of T-cells primed for myelin antigens, by studies of IFN-gamma secretion in response to antigen in vitro, showed that both HMSN I and other polyneuropathy patients had low (but significant) numbers of T-cells recognizing whole PNS-myelin. Increased numbers of IgG- and IgM-producing cells were found in blood and bone marrow in the HMSN I patients. Patients with both HMSN I and the other polyneuropathies had few cells in peripheral blood and in bone marrow producing antibodies binding to P2, MAG and MBP in a solid phase immunospot assay. Many cells in the cerebrospinal fluid produced antibodies against MAG. Thus, there was a strong general activation of B- and T-cells in HMSN I while the immunity directed toward peripheral nerve was only slightly elevated. It is an open question if this immune activation is related to the primary gene defect or a secondary event to the nerve damage. The pathogenetic importance of the immune response in maintaining the nerve damage in HMSN I is unclear.

Adult↗
PubMed1992

Virus-reactive and autoreactive T cells are accumulated in cerebrospinal fluid in multiple sclerosis.

Elevated numbers of B cells--plasma cells secreting antibodies to measles and mumps virus, and to myelin associated glycoprotein (MAG), one of several putative myelin autoantigens--have previously been reported in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS), while it is unknown if corresponding T cell reactivities occur. We have defined the T cell reactivities to measles and mumps virus and to MAG in an immunospot assay which is based on the detection of secretion of interferon-gamma (IFN-gamma) by single cells upon stimulation with specific antigen in short term cultures. Patients with MS had higher numbers of MAG-reactive T cells in blood compared to controls, while no differences were observed for measles or mumps virus-reactive T cells. In CSF, elevated numbers of MAG-reactive T cells and also of measles- and mumps-reactive T cells were found in patients with MS compared to other neurological diseases. A strong accumulation of antigen-reactive T cells was observed in the MS patients' CSF compared to blood. The magnitude of these T cell reactivities did not correlate with clinical MS variables. The T cell repertoire in MS thus includes, besides myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, also MAG and, in addition, measles and mumps virus. It is not clear whether these T cell reactivities accumulated in the CSF have importance for the pathogenesis of MS or reflect phenomena secondary to myelin damage, or result from both these alternatives.

Adolescent↗
PubMed1992

Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats.

The influence of the selective serotonin (5-HT) reuptake inhibiting antidepressant zimeldine and its metabolite norzimeldine was tested on experimental allergic neuritis (EAN) in Lewis rats, which is an animal model of the Guillain-Barré syndrome (GBS) in man. Zimeldine and norzimeldine both suppressed clinical signs of actively induced EAN when given at a dose of 20 mg/kg/day intraperitoneally via osmotic pumps. The effects of zimeldine, its metabolites norzimeldine and CPP 200 as well as of the antidepressants clomipramine, imipramine and maprotiline on in vitro immune response were tested. Thereby we used an immunospot assay for interferon-gamma (IFN-gamma) produced by lymph node mononuclear cells (MNC), which reflects number of memory T lymphocytes activated by antigen or lectin, in this experiment bovine peripheral nerve myelin (BPM) and phytohemagglutinin (PHA), respectively. In the IFN-gamma secretion assay zimeldine, CPP 200, clomipramine and maprotiline all in a concentration-dependent mode reduced the number of IFN-gamma secreting cells while norzimeldine and imipramine did not affect the IFN-gamma secretion. In assays for proliferation in response to antigen or lectin, the concentration 10(-4) M was judged toxic for all substances tested, and at concentrations below that all but zimeldine showed a dose-dependent slight reduction of MNC proliferation. The action of several drugs on induced T cell secretion of IFN-gamma suggests that the mechanisms for the suppressive effect of zimeldine and norzimeldine on EAN symptoms can be due to an action on myelin T cell autoreactivity. All the monoamine reuptake inhibiting antidepressants tested in this study showed immunomodulatory effects by either a reduction of the number of IFN-gamma-secreting cells or the MNC proliferation. These observations call for further studies of immunological mechanisms in the pathogenesis of mental disorders as well as on the potential role of drugs acting on the monoamine systems in the treatment of recognized autoimmune diseases.

Animals↗
PubMed1992

The light chain of tetanus toxin inhibits calcium-dependent vasopressin release from permeabilized nerve endings.

The effects of tetanus toxin and its light and heavy chain subunits on vasopressin release were investigated in digitonin-permeabilized neurosecretory nerve terminals isolated from the neural lobe of the rat pituitary gland. Exocytosis was induced by challenging the permeabilized nerve endings with micromolar calcium concentrations. Tetanus toxin inhibited vasopressin release only in the presence of the reducing agent dithiothreitol. This effect was irreversible. The purified light chain of tetanus toxin strongly inhibited exocytosis in a dose-dependent manner with half-maximal effect at c. 10 nM. The action of the light chain was observed after only 2.5 min of preincubation. Separated heavy chain subunit had no effect on hormone secretion. Inhibition of vasopressin release could be prevented by preincubating the light chain of tetanus toxin with an immune serum against tetanus toxin. The data clearly demonstrate that in mammalian neurosecretory nerve endings tetanus toxin acts at a step downstream from the activation by Ca2+ of the exocytotic machinery and that the functional domain of this toxin is confined to its light chain.

Animals↗
PubMed1992

Calcium antagonists suppress experimental allergic neuritis (EAN).

We examined the influence of Ca++ antagonist drugs on immune response and the clinical course of experimental allergic neuritis (EAN). The Ca++ antagonists verapamil and flunarizine suppressed actively induced EAN in Lewis rats in a dose-dependent fashion when given continuously by osmotic pumps from the day of immunization. If given from onset of clinical signs, day 10 after immunization, verapamil alone had therapeutic effects. The beneficial effects of the drugs seem to be mediated primarily by an action on the autoimmune response, since in vitro lymphocyte proliferation in response to nervous tissue antigens was dose-dependently inhibited by both drugs, whereas the in vitro conductivity of demyelinated sciatic nerve was not significantly affected by the Ca++ antagonists. The suppressive effect on lymphocyte proliferation could partially be bypassed by protein kinase C activating phorbol ester alone or in combination with the Ca++ ionophore ionomycin, confirming a non-toxic effect of the Ca++ antagonists on lymphocytes.

Action Potentials↗
PubMed1992

Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of European Bone Marrow Transplant Group.

Data on 49 allogeneic bone marrow transplant (BMT) recipients who developed interstitial pneumonia due to cytomegalovirus (CMV) were collected retrospectively. All patients were treated with ganciclovir and high doses of intravenous immune globulin, although types of immune globulins and schedules of treatment varied. Seventeen (35%) of 49 patients responded to treatment. Thirty days after the diagnosis of interstitial pneumonia, the survival rate among patients was 31%. CMV was detected in 81% of patients on whom autopsies were performed. The survival rate among patients who received total body irradiation (TBI) was significantly lower (11 [27%] of 41) than that among patients who did not receive TBI (six [75%] of eight; odds ratio = 12.3; P = .009). No other factor, including age, grade of graft-versus-host disease, types and dose of immune globulin used, or dose of ganciclovir, was correlated to survival. These results show that although survival of allogeneic BMT recipients with CMV interstitial pneumonia has improved, more than one-half of the patients still died of pneumonia. Thus, both prophylaxis for and treatment of CMV infection must be improved.

Adolescent↗
PubMed1992

Myelin antigen reactive T cells in cerebrovascular diseases.

T cell reactivities to the putative autoantigens myelin basic protein (MBP), MBP peptides with amino acid residues 110-128 and 148-165, and myelin proteolipid protein (PLP) were examined in patients with acute ischaemic cerebrovascular disease (CVD) and, for comparison, in patients with inflammatory neurological diseases and other neurological diseases. A quantitative measure of these T cell reactivities was obtained by assessing numbers of T cells among blood and cerebrospinal fluid (CSF) mononuclear cells that secreted IFN-gamma in response to antigen in vitro. Higher numbers of T cells reactive with each of these four antigens were detected in peripheral blood from patients with CVD compared with patients of the two control groups. Among blood cells from the CVD patients, their average number was 2.3-4.2/10(5) mononuclear cells. MBP reactive T cells were several-fold enriched in the CSF of CVD patients. The findings strongly suggest that brain damage in context with acute CVD leads to an in vivo expansion of myelin reactive T cells.

Adolescent↗
PubMed1992

The T-cell repertoire in myasthenia gravis involves multiple cholinergic receptor epitopes.

Antibodies against the alpha-subunit of the acetylcholine receptor (AChR) are found in most patients with myasthenia gravis and are considered to contribute to the receptor damage which leads to the characteristic signs and symptoms of the disease. This B-cell response is T-cell driven. Elevated T-cell reactivities to AChR and its alpha-subunit have been described in myasthenia gravis, and AChR alpha-subunit peptide reactive T-cell lines and clones preferentially recognizing certain defined sequence segments have been reported, thereby disclosing the possibility of specific immunotherapy. We have defined the T-cell repertoire to AChR, its alpha-subunit and the synthetic peptide sequences 100-117, 113-130, 143-163, 161-179, 207-225, 221-240, and 235-255 of the alpha-subunit in an immunospot assay which is based on secretion of interferon-gamma (IFN-gamma) by individual memory T cells upon stimulation with specific antigen in short-term cultures. Most patients with myasthenia gravis displayed T-cell reactivities to 1 to 6 different peptides. The mean numbers of T cells recognizing individual peptides varied in the myasthenia gravis patients between 1 per 77,000 and 1 per 167,000 peripheral blood mononuclear cells. None of the seven peptides evaluated could be identified as an immunodominant T-cell epitope, and any of them was found to dominate in individual patients. The numbers of T cells reacting with AChR and recombinant human AChR alpha-subunit were slightly higher (mean numbers 1 per 26,000 and 1 per 50,000 mononuclear cells, respectively). Such cells, as well as AChR alpha-subunit peptide reactive T cells, were also found in patients with other neurological diseases and in healthy subjects, but at lower frequencies and numbers. In myasthenia gravis, the elevated numbers of memory T cells recognizing multiple AChR alpha-subunit peptides may be crucial for the development of the disease, and the IFN-gamma released by such T cells might be important for its perpetuation.

Adolescent↗
PubMed1992

An immunogenetic heterogeneity in multiple sclerosis.

Two clinical forms of multiple sclerosis (MS), primarily chronic progressive MS (PCP MS) and relapsing/remitting MS (R/R MS) have been shown to differ in several respects. The results of genomic HLA class II typing with restriction fragment length polymorphism analysis of 62 MS patients from Western Norway, 42 with R/R MS and 20 PCP MS, are reported on here. As in previous studies of Swedish patients, the haplotype DRw17(3), DQw2 was found to be five times more common in R/R MS than in PCP MS. This finding supports the hypothesis that R/R and PCP MS are immunogenetically separate entities. In contrast with a previous investigation of Norwegian MS patients, no association of MS with glutamine at position 34 of the HLA-DQ alpha chain or with defined sequences of the HLA-DQB1 gene was found.

Adult↗
PubMed1992

Influence of the freezing-thawing-washing procedure on the cytomegalovirus DNA content of cellular blood products.

There is a proven relation between cytomegalovirus (CMV) infection in seronegative immunocompromised patients and transfusion of random CMV unscreened cellular blood products (BP), where the leukocytes are thought to be the vector of transmission. We examined whether freezing, thawing, and washing, in attempt to reduce the quantity of leukocytes, also reduces the CMV-DNA-carrying cells of BP of CMV-seropositive donors and their infectivity for fibroblasts, using the polymerase chain reaction (PCR). The leukocyte contamination of the thawed-washed erythrocyte concentrates was < 1 x 10(8)/l and of the thawed-washed platelet concentrates, approximately 2.5 x 10(8)/l. All plasma samples and most samples of BPs of the CMV-seronegative controls were PCR-CMV-DNA-negative. The differences of the PCR results with the samples of CMV-seropositive donors before and after freezing were not significant. Thus we concluded that freezing-thawing-washing of cellular BP could not eliminate all CMV-DNA-bearing leukocytes. Plasma carries low risk for CMV infection, if at all.

Blood Component Removal↗