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Biomedical subjects

A K Lefvert

Publications and source records attributed to A K Lefvert.

At least 91 records · Page 5Linked to original sources
PubMed1994

Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients.

The pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), induction of anti-GM-CSF antibodies, and clinical effects related to the induction of the antibodies were analyzed in patients with metastatic colorectal carcinoma (CRC) who were not on chemotherapy (n = 20, nonimmunocompromised patients). rhGM-CSF (250 micrograms/m2/d; Escherichia coli-derived) was administered subcutaneously for 10 days every month for 4 months. Eight patients with multiple myeloma (MM) on intensive chemotherapy followed by rhGM-CSF treatment were also included (immunocompromised patients). After a single injection of GM-CSF at the first cycle in CRC patients, the maximum calculated concentration (Cmax) was 5.24 +/- 0.56 ng/mL; the half life (T1/2) was 2.91 +/- 0.8 hours; and the area under the concentration curve (AUC) was 30.86 +/- 6.03 hours x ng/mL (mean +/- SE). No anti-GM-CSF antibodies were detected. During the subsequent cycles, 95% of the CRC patients developed anti-GM-CSF IgG antibodies, which significantly altered the pharmacokinetics of rhGM-CSF at the third and fourth cycles with decreased Cmax (2.87 +/- 0.57 ng/mL; P < .05), T1/2 (1.57 +/- 0.2 hours; P < .05), and AUC (14.90 +/- 4.10 hours x ng/mL; P < .005). The presence of anti-GM-CSF antibodies significantly reduced the GM-CSF-induced enhancement of granulocytes, and there was a clear tendency for a decreased increment of monocytes. Antibodies diminished systemic side effects of rhGM-CSF. Only 1 of 8 MM patients showed a very low anti-GM-CSF antibody titer after GM-CSF therapy, as shown by enzyme-linked immunosorbent assay and Western blot. Therefore, in nonimmunocompromised patients, exogenous nonglycosylated GM-CSF induced an anti-GM-CSF IgG antibody response in practically all patients, which seemed to be of clinical significance. In immunocompromised patients, virtually no significant antibody response was shown.

Adolescent↗
PubMed1994

Idiotype- and anti-idiotype-reactive T lymphocytes in myasthenia gravis. Evidence for the involvement of different subpopulations of T helper lymphocytes.

Patients with myasthenia gravis have peripheral blood T cells that are stimulated to secrete IFN-gamma and IL-2 by human monoclonal anti-acetylcholine receptor and anti-idiotypic Abs. The human CD4+ Th cells may be subdivided into different subsets according to the pattern of cytokine production. To elucidate the subgroup of T cells involved in myasthenia gravis, we have analyzed IL-4-, IFN-gamma-, and IL-2-secretion patterns induced by two human disease-specific mAbs, one idiotypic and one anti-idiotypic Ab. T cells stimulated to secrete one or more of the cytokines were found in 33 of 34 patients. The idiotypic Ab stimulated IL-4 secretion in 19 of 34 patients, IFN-gamma secretion in 26 of 34 patients, and IL-2 secretion in 25 of 34. The anti-idiotypic Ab induced IL-4 secretion in 9 of 34 patients, IFN-gamma secretion in 29 of 34 patients, and IL-2 secretion in 28 of 34 patients. These T cell responses were MHC class II-restricted. According to the cytokine-secretion patterns, Id-reactive T cells might correspond to both Th1/Th2 and/or Th0 cells. The anti-idiotypic Ab more frequently induced a Th1-type response. This study indicates that different subsets of T lymphocytes are involved in the idiotypic network in myasthenia gravis, and that these functionally different T cells may participate in the immunoregulation of the disease.

Antibodies, Monoclonal↗
PubMed1994

Acetylcholine receptor-reactive T cells in myasthenia gravis: evidence for the involvement of different subpopulations of T helper cells.

Patients with myasthenia gravis have a high prevalence of acetylcholine receptor-specific T lymphocytes in the peripheral blood. Our earlier study shows that these T lymphocytes are stimulated to secrete interferon (IFN)-gamma and interleukin (IL)-2 in response to the autoantigen. Such stimulated T cells may be subdivided into different subsets according to the pattern of cytokine production. In the present study we have investigated the subpopulations of cells by analyzing their IL-4, IFN-gamma and IL-2 secretion pattern. Autoantigen-stimulated IL-4 secretion was found in 55% of the patients, IFN-gamma secretion in 86% and IL-2 secretion in 72%. T lymphocytes from all patients who responded with increased IL-2 secretion also showed increased IFN-gamma secretion. Stimulated IL-4 secretion was detected both in the presence and absence of stimulated IFN-gamma secretion. Depletion of monocytes/macrophages from peripheral blood mononuclear cell preparation and treatment of the cells with a mouse anti-human HLA-DR antibody abolished the secretion of IFN-gamma and IL-4. There were positive correlations between the numbers of IFN-gamma- and IL-2-secreting T cells and the numbers of B cells secreting antibodies against the acetylcholine receptor. Our results show that acetylcholine receptor-stimulated T lymphocytes secrete IL-4, IFN-gamma and/or IL-2. This T cell response is major histocompatibility complex (MHC) class II-restricted and monocyte/macrophage-dependent. Our study indicates that both Th1/Th2 or Th0 subpopulations of the T lymphocytes are involved in the autoimmune response in myasthenia gravis.

Adolescent↗
PubMed1994

Anti-idiotypic B lymphocytes in patients with monoclonal gammopathies.

The prevalence of peripheral blood B cells secreting antibodies reacting with the F(ab')2 fragment of monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy controls. An enzyme-linked immunospot assay allowed direct visualization of antibody producing B cells. All patients had B cells producing antibodies to autologous or allogeneic monoclonal IgG. Autoreactive cells were found more frequently than alloreactive cells in seven out of nine patients with MGUS and three out of four patients with MM. The same frequency of alloreactive cells in the patient groups was detected in healthy individuals. These findings show the existence of B cells producing anti-idiotypic antibodies which could be a part of an idiotypic network in monoclonal gammopathies.

Aged↗
PubMed1994

Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity.

We treated a patient with severe myasthenia gravis with a chimeric (murine/human) anti-CD4 monoclonal antibody (cM-T412) for 7 days and followed the therapeutic effect by standardized muscle function tests, single-fiber electromyography, and immunologic examinations of disease-specific B- and T-cell functions. Clinical and electrophysiologic improvement began within 4 days, lasted for 3 months, and was maximal between days 16 and 58. The CD4+ lymphocytes decreased to a minimum of 80 cells per microliters of peripheral blood, recovered slowly during the first year of follow-up, and did not correlate with changes in disease severity. T-cell stimulation by human acetylcholine receptor was abolished by the treatment but became detectable at the time of worsening of symptoms. The concentration of acetylcholine receptor antibodies in serum was not decreased by the treatment. The results suggest that anti-CD4 antibody administration could be effective in the treatment of severe myasthenia gravis and indicate that acetylcholine receptor-specific T lymphocytes might contribute to the disturbed neuromuscular transmission in the disease.

Antibodies↗
PubMed1993

Mononuclear leukocytes exposed to oxidized low density lipoprotein secrete a factor that stimulates endothelial cells to express adhesion molecules.

In animals fed a hypercholesterolemic diet, development of atherosclerosis is preceded by attachment of mononuclear leukocytes to the arterial endothelium. Early lesions begin to develop as monocytes migrate into the intima and ingest lipids. A major part of these lipids is believed to be derived from oxidatively modified low density lipoprotein (LDL). In the present study we demonstrate that human mononuclear leukocytes exposed to low concentrations of copper-oxidized LDL secrete one or several factors that stimulate the expression of intercellular adhesion molecule-1 (ICAM-1, CD54), vascular cell adhesion molecule (VCAM-1) and endothelial selectin (E-selectin-1, ELAM-1), whereas native LDL was found to be without effect. Exposure of endothelial cells to non-conditioned medium containing oxidized LDL did not influence the expression of adhesion molecules. Incubation of endothelial cells with conditioned medium from mononuclear cells grown in the presence of oxidized LDL also resulted in a three-fold increase in the binding of monocytoid U937 cells. The present findings suggest that mononuclear leukocytes exposed to oxidatively modified LDL in early atherosclerotic lesions may stimulate the recruitment of other leukocytes by secreting cytokines which induce the expression of adhesion molecules on the endothelium.

Cell Adhesion↗
PubMed1993

Human muscle acetylcholine receptor reactive T and B lymphocytes in the peripheral blood of patients with myasthenia gravis.

The prevalence of T and B cells reactive with the acetylcholine receptor (AChR) of human skeletal muscle was studied in 33 patients with myasthenia gravis (MG), 18 patients with other neurological diseases (OND) or autoimmune disorders (AD) and 27 age- and sex-matched healthy controls. T cell stimulation was estimated by enumerating cells secreting interferon (IFN)-gamma and interleukin (IL)-2 in response to the AChR, whereas B cell reactivity was estimated by enumerating cells secreting IgG antibodies binding to the AChR. AChR-reactive T cells were increased in the peripheral blood of patients with MG as compared to patients with OND, AD and healthy individuals. Of the patients with MG, 29/33 (87.7%) had numbers of IFN-gamma secreting cells higher than the mean +/- 2 SD of the mean of controls as compared to 4/18 (22.2%) of patients with OND or AD and 2/27 (7.4%) of the controls. The mean value of the numbers of AChR-reactive T cells in the patients with MG was 19.6/10(5) PBMC, corresponding to 1/5100 PBMC. Comparable results were obtained also for IL-2-secreting cells. Anti-AChR IgG antibody-secreting cells were detected in the blood of 30/33 (91%) of the patients with MG, 3/18 (16.7%) of the patients with OND or AD and 2/25 (8%) of the controls. The mean value of the antibody-secreting cells in MG was 11.7 cells/10(6) PBMC corresponding to 1/70,400 PBMC in the patients with MG, compared to a mean value of antibody-secreting cells in the patients with OND or AD of 0.33 and controls of 0.16 cells/10(6) PBMC.

Adolescent↗
PubMed1993

T-cell stimulation induced by idiotypes on monoclonal immunoglobulins in patients with monoclonal gammopathies.

The stimulation of peripheral blood mononuclear cells by purified autologous and/or allogeneic monoclonal IgG was studied in five patients with multiple myeloma (MM), nine patients with monoclonal gammopathy of undetermined significance (MGUS) and six healthy individuals. Single cells secreting IFN-gamma or IL-2 were identified using an enzyme-linked immunospot assay. Patients' cells were preferentially stimulated by autologous monoclonal IgG at low concentrations (1-100 pg/ml), while 100 ng/ml or higher stimulated T cells both from patients and, to a lesser degree, healthy individuals. This biphasic dose-response of T-cell stimulation by autologous monoclonal IgG was reproduced in all patients. The numbers of cells secreting IFN-gamma and IL-2 in response to allogeneic IgG were significantly lower than the numbers obtained using autologous IgG in patients with MM and MGUS. Cells from healthy individuals were stimulated by allogeneic monoclonal IgG, but to a lesser extent. The results of this study support the presence of idiotype-reactive T cells in patients with MM and MGUS and also may suggest a general but less pronounced T-cell reactivity to monoclonal IgG among these patients.

Aged↗
PubMed1993

Recurrent angioedema caused by circulating immune complexes containing antibodies against bovine proteins.

A 27-year-old woman with severe recurrent angioedema and urticaria since 5 years was found to have high levels of circulating immune complexes in the peripheral blood. These immune complexes contained antibodies against bovine serum albumin. Elimination of bovine products from the diet resulted in disappearance of immune complexes within 2 days and addition again to the diet led to reappearance within 24 h. The patient has now been in complete remission during 4.5 years under treatment with a diet free of bovine proteins but containing products from chicken, egg, pork and fish. The immune complexes have not reappeared. Thus, immune complexes containing antibodies against alimentary antigens can provoke acute vascular damage manifested as angioedema and urticaria. In such cases, elimination of the causative antigen from the diet can result in patient being cured.

Adult↗
PubMed1992

Idiotypic and antiidiotypic T and B lymphocytes in myasthenia gravis.

The prevalence of Id and anti-Id T and B cells as measured by their reactivities with two human mAb, one antiacetylcholine receptor mAb and one anti-Id mAb, was studied in 38 patients with myasthenia gravis and in 27 healthy individuals. Id and anti-Id T cells were estimated by enumerating the numbers of cells secreting IFN-gamma in response to 10 pg/ml of the human mAb. T cell stimulation, measured as numbers of IFN-gamma-secreting cells that exceeded the mean + 2 SD of controls, was induced by the Id mAb in 78.9% of the patients and in 7.4% of the controls, whereas the anti-Id mAb-stimulated T cells in 55.3% of the patients and in 3.7% of the controls. The mean value of the Id and anti-Id-reactive T cells in the patients was 18.3/10(5) and 10.1/10(5) PBMC, respectively. B cells secreting IgM antibodies binding to the human mAb were increased in patients with myasthenia gravis compared to healthy controls. Seventy-five percent of the patients and 12% of the controls had B cells secreting IgM antibodies binding to the Id mAb, although 89% of the patients and 16% of the controls had B cells secreting IgM antibodies binding to the anti-Id mAb. The mean value of B cells secreting IgM antibodies binding to Id or anti-Id mAb in the patients were 7.4 cells/10(6) and 5.5 cells/10(6) PBMC, respectively. We conclude that Id and anti-Id T and B cells are present in myasthenia gravis. These methods allow a quantitative estimation of T and B cells with defined specificities and thus a way of mapping the repertoire of lymphocytes.

Adolescent↗
PubMed1992

Human anti-acetylcholine receptor antibodies use variable gene segments analogous to those used in autoantibodies of various specificities.

The production of autoantibodies to the nicotinic acetylcholine receptor are responsible for many of the neurological symptoms observed in myasthenia gravis. An understanding of the structural organization of the anti-receptor antibodies may help to define the role of these antibodies in the pathogenesis of this disease. The nucleotide sequences of the heavy and light chains of three human monoclonal anti-receptor antibodies isolated from peripheral blood lymphocytes from two patients with myasthenia gravis were analyzed. In addition, the structure of an anti-idiotypic antibody was studied. The VH and VL gene segments used in the anti-receptor antibodies appear to be derived from the same repertoire as gene segments that have been found in other autoantibodies isolated from patients with various autoimmune diseases. The IgM anti-receptor antibodies are direct copies of germline gene segments, while the structures of the IgG anti-receptor antibody and the anti-idiotypic antibody appear to be mutated suggesting that they have undergone antigenic selection.

Amino Acid Sequence↗
PubMed1992

Beta 2-adrenergic receptor antibodies in myasthenia gravis.

Although autoantibodies against the nicotinic acetylcholine receptor are the characteristic feature of the autoimmune disease myasthenia gravis (MG), no strong correlation is found between the autoantibody titer and the degree of clinical severity. Numerous studies have attempted to detect the presence of other autoantibody populations that might have a role in the pathology of the disease. We report, for the first time, that 18% of the MG patients we screened have antibodies in their serum to a peptide corresponding to the second extracellular loop of the human beta 2-adrenergic receptor (residues 172-197). Affinity purified antibodies to the beta 2-adrenergic receptor peptide 172-197 reacted with the human beta 2-adrenergic receptor protein obtained from transfected E. coli cell membrane extracts, but did not cross-react with the human AChR. Sufficient material was obtained from nine MG patients and it was found that the gamma globulin fraction from these patients immunoprecipitated the receptor, and that affinity purified IgG to peptide 172-197 competed for receptor binding with the beta-antagonist iodo-cyanopindolol. Using truncated peptides or amino acid modification procedures, no immunodominant B-cell epitope could be detected within region 172-197. Thus, a subpopulation of MG patients possesses anti-beta 2-adrenergic receptor antibodies which are a distinct set of autoantibodies with possible pharmacological activity.

Amino Acid Sequence↗
PubMed1992

T cells with specificity for idiotypic determinants on human monoclonal autoantibodies in myasthenia gravis.

The activation of T cells from 46 patients with myasthenia gravis and 28 healthy individuals by two human monoclonal autoantibodies was studied. B-cell clones were produced by transformation of peripheral lymphocytes from a patient using Epstein-Barr virus and subsequent cloning. Two myasthenia-specific autoantibodies, one anti-receptor-antibody and one antiidiotypic antibody, both carrying separate recurrent idiotopes, were used in this study. Single activated T cells were identified by their secretion of IL2 and IFN gamma using a cell enzyme-linked-immunosorbent technique. The idiotypic antibody activated T cells in patients but not in most of the controls at concentrations of 1 pg/ml and 10 pg/ml. High concentrations of antibody resulted in T-cell activation in both groups. A similar dose-response pattern was recorded using the antiidiotypic antibody. Incubation with the idiotypic antibody resulted in T-cell stimulation, measured as numbers of IFN gamma-secreting cells that exceeded the mean +2 SD of controls, in 78% of patients and in 7% of the healthy individuals (p less than 0.001). The antiidiotypic antibody activated T cells in 50% of patients and in 4% of the healthy individuals (p less than 0.001). T-cell activation measured as numbers of IL2-secreting cells showed a difference between patients and controls which was as significant as for IFN gamma secretion. The results demonstrate the presence of T cells with specificity for disease-specific determinants on idiotypic and antiidiotypic antibodies in myasthenia gravis.

Adult↗