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Biomedical subjects

A K Lefvert

Publications and source records attributed to A K Lefvert.

At least 109 records · Page 6Linked to original sources
PubMed1992

T-cell epitopes on the human acetylcholine receptor alpha-subunit residues 10-84 in myasthenia gravis.

In myasthenia gravis the production of anti-acetylcholine receptor antibodies is modulated by acetylcholine receptor-specific T cells. Most B- and T-cell epitopes are located on the alpha-subunit of the receptor. In order to map the fine specificity of the antigen-specific T cells in myasthenia gravis, T-cell stimulation in response to 70 hexapeptides was studied in 24 patients and 24 healthy individuals. The hexapeptides overlapped with one amino acid and represented residues 10-84 of the NH2-terminal part of the alpha-subunit of the receptor. The IFN-gamma secretion from single T cells was used to detect T-cell stimulation. A significant difference in the T-cell response to several of the peptides was found between patients and healthy controls. The majority of the hexapeptides induced T-cell stimulation in at least one of the patients. Peptide-induced T-cell stimulation was evident in all but one of the patients. The results indicate that different epitopes and multiple T-cell clones are involved in the T-cell recognition of the acetylcholine receptor.

Adult↗
PubMed1992

Induction of T-cell activation by oxidized low density lipoprotein.

Oxidation and scavenger receptor-mediated uptake of low density lipoprotein (LDL) in intimal macrophages are believed to be key events in the development of atherosclerosis. We report here that oxidized LDL increases DNA synthesis, expression of HLA-DR, and interleukin-2 receptors in T cells. The stimulatory effect of oxidized LDL was not due to a direct effect on T cells but required the presence of monocytes. Oxidized LDL also stimulated the release of interleukin-1 beta from monocytes. The maximal effect of oxidized LDL on T-cell activation and interleukin-1 beta release occurred at a concentration of 1 micrograms/ml. Native LDL also had the capacity to activate T cells, although only at higher concentrations. The stimulatory effect of both native and oxidized LDL was inhibited by superoxide dismutase. Monocytes as well as T cells were found to have the ability to oxidize LDL, suggesting that the stimulatory effect of native LDL may arise as a result of LDL oxidation during incubation with monocytes and T cells. The results suggest that oxidized LDL may activate T cells in atherosclerotic lesions.

Antigens, Surface↗
PubMed1992

Follow-up study of muscle function in children of mothers with myasthenia gravis during pregnancy.

Most infants whose mothers have myasthenia gravis are healthy at birth, but 10% to 15% have a transient neonatal form of myasthenia gravis. In this study, the muscular function and neuromuscular transmission were examined in 31 children, aged 3 months to 31 years (median, 10 years), of 15 myasthenic mothers. Eleven of these children had had the neonatal form of myasthenia gravis. The children were examined clinically and with neurophysiologic methods. Blood samples were taken for HLA typing, creatine kinase levels, and myoglobin and acetylcholine receptor antibody studies. Twenty-nine of the 31 children had no signs of neuromuscular disease. Two children (who had had neonatal myasthenia gravis) had a moderate stationary myopathy, probably unrelated to the myasthenia gravis of their mother. Creatine kinase levels were normal for all subjects. Acetylcholine receptor antibody levels were similar to those of a control population. The HLA type B8 antigen was not significantly more prevalent in the children who had had neonatal myasthenia gravis than in the healthy children. Neonatal myasthenia gravis in a previous sibling was the only factor in the material that predicted the occurrence of myasthenic symptoms in the neonatal period.

Adolescent↗
PubMed1992

Levels of CD5+ B lymphocytes do not differ between patients with myasthenia gravis and healthy individuals.

CD5+ B cells might be involved in autoimmunity mainly as autoantibody-producing cells. To investigate the possible role of these cells in myasthenia gravis, we studied the numbers of CD5+ B cells, CD5- B cells, and CD19+ B cells as well as CD5+ T cells in the peripheral blood from 31 patients with myasthenia gravis and 31 healthy individuals. Both absolute percentages (percent of peripheral blood mononuclear cells) and relative percentages (percent of total CD19+ B cells) of CD5+ B cells were the same in patients as in controls. The numbers of CD5- B cells and CD19+ B cells were the same in both groups, whereas CD5+ T cells were lower in the patients. There was no correlation between clinical stage, sex, thymectomy, or pathology of thymus and the levels of CD5+ B cells, CD5- B cells, or CD19+ B cells. Patients treated with azathioprine had lower levels of CD5+ B cells than untreated patients and controls. Our results show that patients with myasthenia gravis have the same levels of CD5+ B cells as healthy individuals.

Adult↗
PubMed1992

Proteinuria and renal function in relation to renal morphology. A clinicopathological study of IgA nephropathy at the time of kidney biopsy.

At the time of kidney biopsy the pattern of urinary protein excretion (UPE) and renal function were studied in 54 patients (age 16-62 years) with IgA nephropathy (IgAN). Serum and urinary albumin (alb), IgG, beta-2-microglobulin and creatinine were analysed, and excretion rates (UV) and clearances were calculated. The glomerular filtration rate (GFR) was determined by plasma 51Cr-EDTA clearance (51Cr-EDTA) and by 24-hour creatinine clearance (C-Cr 24 h). Glomerular mesangial (volume expansion and cell proliferation), tubulo-interstitial (fibrosis and inflammation) and vascular lesions were classified semiquantitatively on a five-degree scale, and the percentage of glomeruli showing global sclerosis, segmental sclerosis and cellular crescents was calculated. One third of our patients had reduced renal function, three patients uremia and 70 per cent of the patients overt albuminuria. The mean GFR was reduced in microalbuminurics and further decreased in albuminurics and nephrotics. A lower GFR and more proteinuria were found in the patients with more advanced morphological lesions also when the uremic patients were excluded. Segmental glomerular sclerosis correlated with GFR as well as with UalbV and UIgGV, while global sclerosis correlated only with GFR. UalbV and UIgGV also correlated with the extent of interstitial damage but not with mesangial lesions. In summary an accurate determination of GFR and UPE at the time of the kidney biopsy may give an indication of the extent of renal damage. A lowered GFR was also found in mild proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Anti-idiotypic immunity as a potential regulator in myeloma and related diseases.

In this paper some recent and partly preliminary results on anti-idiotypic immunity against clonal B cells in human monoclonal gammopathies are summarized. B cell lines producing antibodies to idiotypic determinants on autologous monoclonal immunoglobulin could be propagated after activation with Epstein-Barr virus of peripheral blood lymphocytes from patients with MGUS and MM clinical stage I but not from untreated persons with advanced MM. Blood T lymphocytes from patients with MGUS and Waldenström's macroglobulinemia were activated to DNA synthesis and production of interleukins by the autologous M protein. In another series of experiments T cell clones raised from patients with MM clinical stage I and MGUS bound F(ab')2 fragments of the autologous M protein and were stimulated to DNA synthesis by the idiotope-bearing protein. Control experiments demonstrated the specificity for idiotypic determinants. Ten of eleven clones were CD4-/CD8+. Finally, using a panel of 8 mAbs to alpha/beta V region epitopes, we noted a clonal expansion of CD4+ and CD8+ T cells in MGUS and MM patients.

Animals↗
PubMed1991

Establishment of idiotype bearing B-lymphocyte clones from a patient with monoclonal gammopathy.

B-lymphocyte clones bearing an idiotypic Ig structure, which could also be found on the serum M-component, have been isolated from peripheral blood of a patient with monoclonal gammopathy (MG) using an immune-rosetting technique and limiting dilution. The majority of the cells had the surface phenotype id+/CD19+/CD20+/CD21+ or id+/CD19+/CD20+/CD21-. Some of the clones originated from spontaneous outgrowth of lymphocytes and some were derived from in vitro Epstein-Barr virus-infected lymphocytes. Three of the B-lymphocyte clones and the patient's bone marrow plasma cells appeared to have clonal identity as shown by the same Ig heavy chain gene rearrangements in Southern blot analysis using a JH probe. The study further supports the notion that the peripheral blood of patients with MG contains B lymphocytes that belong to the tumor clone.

Antibodies, Monoclonal↗
PubMed1991

Generation of T cell clones binding F(ab')2 fragments of the idiotypic immunoglobulin in patients with monoclonal gammopathy.

Lymphocytes from two patients with multiple myeloma stage I and one patient with monoclonal gammopathy of undetermined significance were found to proliferate specifically in response to low concentrations of F(ab')2 fragments of the autologous M component. T cell clones isolated from repeatedly stimulated cultures bound specifically the autologous idiotype and proliferated after addition of soluble idiotype and exogenous interleukin-2. The majority of clones were CD8+ and showed negligible staining for CD4. Idiotype-binding clones could not be isolated from cultures of lymphocytes from a healthy control stimulated under the same conditions. The study provides support for the existence of idiotype-reactive T cells in monoclonal gammopathies. Such cells might have a regulatory role on the tumor cell clone and may be important for a future therapeutic approach.

Cell Division↗
PubMed1991

Defective T lymphocyte function in nonthymectomized patients with myasthenia gravis.

In vitro functional properties of peripheral blood mononuclear cells were evaluated in 29 patients with myasthenia gravis and in 11 healthy controls. Spontaneous cell proliferation was higher in patients than in controls. The production of interleukin-2 and interferon-gamma and the proliferative response to different mitogens were reduced in the patients. A positive correlation was found between the production of interleukin-2 and interferon-gamma. These defects in T cell function were the most pronounced in nonthymectomized patients. Patients with severe disease had a higher percentage of cells bearing the interleukin-2 receptor and a higher spontaneous production of tumor necrosis factor alpha in cell culture than in patients with mild disease. There was no difference between patients and controls in the level of soluble interleukin-2 receptor in cell culture supernatants or in sera. The results indicate a partially suppressed T cell function in myasthenia gravis. This defect was less pronounced in patients studied after thymectomy.

Adult↗
PubMed1991

Induction of anti-idiotypic (ab2) and anti-anti-idiotypic (ab3) antibodies in patients treated with the mouse monoclonal antibody 17-1A (ab1). Relation to the clinical outcome--an important antitumoral effector function?

Forty-three patients with metastatic colorectal carcinoma (CRC) were treated with the unconjugated mouse monoclonal antibody (MAb) 17-1A (ab1) only. The presence of antiidiotypic antibodies (ab2) and anti-antiidiotypic antibodies (ab3) were analyzed using an ELISA technique and a mixed hemadsorption assay respectively. Ninety-five percent (41/43) of the patients developed ab2 both of the IgM and the IgG classes. Forty-seven percent (20/43) of the patients had detectable ab3 after therapy, two of them also before administration of MAb 17-1A. Binding in vitro of ab3 (ab1) to CRC cells could be specifically inhibited by ab1. Ab3 bound to human monoclonal antiidiotypic antibodies and to a goat antiidiotypic antibody (ab2). Both these ab2 were directed against MAb 17-1A (ab1). There was a strong correlation between the presence of ab3 and the clinical outcome. Ab3+ patients survived significantly longer than those who did not develop ab3 antibodies, 80 weeks vs 38 weeks (p less than 0.001). A statistically significant correlation was found between the presence of ab3 and the anti-tumor response (CR + PR + MR + SD) (p = 0.01). Thus, induction of an antiidiotypic cascade seems to be an important antitumor effector function of MAb in the treatment of cancer patients.

Antibodies, Anti-Idiotypic↗
PubMed1991

Anti-idiotypic antibodies in patients with monoclonal gammopathies: relation to the tumour load.

The production of anti-idiotypic antibodies from Epstein-Barr virus transformed peripheral blood lymphocytes was analysed in 12 patients with multiple myeloma and monoclonal gammopathy of undetermined significance. A low anti-idiotype production was found in patients with advanced disease (multiple myeloma stage III), whereas the production was high in patients with multiple myeloma stage I and monoclonal gammopathy of undetermined significance (MGUS) (P less than 0.01). The study supports the existence of an immunological network response in patients with monoclonal gammopathies.

Aged↗
PubMed1991

Abnormal T-cell expansion and V-gene usage in myasthenia gravis patients.

To determine the extent of V-gene heterogeneity of blood T lymphocytes in patients suffering from Myasthenia Gravis (MG), we used eight recently available monoclonal antibodies (MoAb), directed against different V alpha and V beta gene products of the variable part of the T-cell receptor (TCR), covering approximately 25% of the alpha/beta T cells in normal peripheral blood (PBL) of healthy individuals. Using a two-colour immunofluorescence method, we could calculate the expression of alpha/beta V segments within the two major T-cell subsets, CD4-/CD8+ and CD4+/CD8- lymphocytes. Twenty-seven per cent (4/15) of the MG patients had T cells showing signs of abnormal expansion. Furthermore, among these expanded T cells, a restricted V beta 12 gene expansion could be seen, in three out of four patients. No correlation between TCR V-gene usage and HLA haplotypes (HLA-A, -B, -DR and -DQ) could be seen. Our data suggest that the majority of MG patients have abnormally expanded T-cell clones. The relevance of these findings is discussed.

Antibodies, Monoclonal↗
PubMed1991

Peripheral blood T lymphocytes in patients with monoclonal gammopathies: expanded subsets as depicted by capacity to bind to autologous monoclonal immunoglobulins or reactivity with anti-V gene-restricted antibodies.

The presence of T cells binding F(ab')2 fragments of the idiotypic immunoglobulin was examined by immunofluorescence in peripheral blood of patients with monoclonal gammopathy. In 3 out of 11 tested patients, 1-15% idiotype-binding T cells of either CD4 or CD8 phenotype were found. In 1 patient both a CD4+ and a CD8+ idiotype-binding T-cell fraction were present. In 1 patient the idiotype-binding T cells also reacted with a mAb directed against the variable parts of the TCR alpha or beta chains, further indicating a clonal origin at the alpha/beta level. 3 patients had an expanded predominant T-cell receptor V gene usage based on the reactivity with the limited panel of TCR mAb, but these "clonal" T cells did not bind the idiotype. The study supports the existence of idiotype-specific T cells in peripheral blood of patients with monoclonal gammopathy. Such cells might have a regulatory role on the monoclonal B-cell clone and may be an important target for immunotherapy.

Aged↗
PubMed1990

Pharmacokinetics of the mouse monoclonal antibody 17-1A in cancer patients receiving various treatment schedules.

Twenty-four patients with metastatic colorectal carcinoma were treated with repeated doses (200-500 mg) of the mouse monoclonal antibody (MAb) 17-1A. Four different treatment schedules were used. The total dose was 1, 3.6, 7.6, and 12 g, respectively. Altogether, 263 infusions were administered. The interindividual variations in the maximum serum concentration at 2 h (max2 h) were large. The mean max2 h value after an infusion of 200 mg was 55 +/- 5 micrograms/ml and after 500 mg, 132 +/- 7 micrograms/ml. Max2 h concentration correlated inversely with the half-life of MAb 17-1A (P less than 0.001). The t1/2 beta for 200 mg was 25.9 +/- 1.4 h and after the administration of 500 mg, 19.8 +/- 1.0 h. The total area under the concentration versus time curve increased when high doses were administered on a continuous basis, in comparison with spaced infusions, thus increasing the exposure of the tumor tissues to MAb 17-1A. The pharmacokinetics of mouse MAb 17-1A are best described by a one-compartment model. All patients developed anti-mouse IgG antibodies and most also IgM antibodies. In the more intensive treatment schedules, the IgG antibody response was suppressed. Induction of high titers of anti-mouse antibodies did not cause clinical problems. Neither did they affect the pharmacokinetics of MAb 17-1A at these dose levels. Therapy was tolerated well. The side effects were mild and of short duration. The gastrointestinal adverse reactions were dose dependent and correlated to serum max2 h concentration. Allergic reactions were rare and easily clinically manageable.

Animals↗
PubMed1990

Incidence and reactivity patterns of skeletal and heart (SH) reactive autoantibodies in the sera of patients with myasthenia gravis.

Serum from patients with myasthenia gravis (MG) contain antibodies to numerous skeletal muscle components in addition to the acetylcholine receptor (AChR). Certain non-AChR skeletal muscle autoantibodies have been shown by absorption to cross-react with cardiac muscle, leading to the designation of 'skeletal and heart' or SH antibodies. This study describes a new procedure for the extraction of human cardiac muscle which allows direct determination of SH antibody reactivity. Serologic evaluation of 17 patients with MG revealed 9/17 (53%) were seropositive for SH antibody to cardiac muscle. Absorption of selected MG serum samples with cardiac muscle extracts, reduced or eliminated reactivity to skeletal muscle in all cases, confirming the presence of cross-reactive antibodies. Immunoblot analysis of cardiac muscle extracts demonstrated several distinct antigenic components, which were unrelated to the acetylcholine receptor or to previously identified striational muscle proteins. Serum samples from individual MG patients displayed different immunoblot reactivity patterns ot the antigens in cardiac muscle extracts, providing the first evidence of multiple heart-reactive SH antibodies in MG.

Antigens↗
PubMed1990

Acetylcholine receptor antibodies in primary biliary cirrhosis: characterization of antigen and idiotypic specificity.

Auto-antibodies against the acetylcholine receptor of skeletal muscle are considered to be the cause of the neuromuscular dysfunction in myasthenia gravis. However, such auto-antibodies also occur in disease states not accompanied by neuromuscular symptoms. Patients with primary biliary cirrhosis have a high prevalence of different auto-antibodies, including antibodies against the acetylcholine receptor. In primary biliary cirrhosis, these anti-receptor antibodies are predominantly of IgM isotype. The IgM antibodies show a broader reactivity with receptors from other species than antibodies from myasthenic patients. Immunoglobulins from patients with primary biliary cirrhosis bear the same receptor antibody-associated idiotypes, but the repertoire is quantitatively different from that found in myasthenia gravis patients. The IgM receptor antibody activity in a serum from a patient with primary biliary cirrhosis could be inhibited by cardiolipin, poly[dT], poly[I], and ssDNA, whereas this antibody activity in serum from a patient with myasthenia gravis was slightly reduced only by cardiolipin. Generally, IgM antibodies from patients with primary biliary cirrhosis had a broader reactivity with polynucleotides and phospholipids than IgG antibodies and antibodies from patients with myasthenia gravis. These results indicate a difference in the fine specificity between acetylcholine receptor antibodies in primary biliary cirrhosis and in myasthenia gravis.

Animals↗