Neuroimmunotoxic effects in offspring of paternal alcohol consumption.
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Alcohol Drinking↗
Biomedical subjects
M G Mutchnick
Publications and source records attributed to M G Mutchnick.
Persistent immune deficiency in patients with alcoholic hepatitis.
T-lymphocyte subset numbers, recall-antigen skin test responses and mitogen-induced lymphocyte proliferation assays were investigated in 12 patients with severe alcoholic hepatitis (AH). Serial studies of these parameters were obtained at intervals of 1 or 2 wk. Patients with AH had lower peripheral blood lymphocyte counts with corresponding decreases in T-cell subset numbers that were persistent in the serial evaluations. T8 cells were disproportionately decreased, with a significant resultant increase in the T4:T8 ratios. Compared with controls, AH patients had significantly smaller cutaneous responses to Candida albicans antigen (p less than 0.05) and mumps antigen (p less than 0.005). Fifty-eight percent of patients were anergic when tested with a battery of four antigens. Patients with AH had increased concanavalin A-, but not phytohemagglutinin-induced lymphocyte proliferative responses. These serial analyses confirm previous observations of cell-mediated immune dysfunction in patients with severe AH. Moreover, there is a persistence of these abnormalities for at least 6 wk after withdrawal from alcohol.
Hepatitis, Alcoholic↗
Localization of immunoreactive thymosin alpha 1 in astrocytes of normal human brain.
We employed an immunocytochemical method to examine human brain for the presence of immunoreactive thymosin alpha 1 (T alpha 1), a peptide derivative of thymic tissue, using a well-characterized antiserum. For cell identification, serial sections were stained with antisera to thymosin beta 4(T beta 4), another thymic peptide that identifies oligodendrocytes, and with anti-glial fibrillary acidic protein (GFAP) antiserum that stains astrocytes in a double-staining technique using avidin-biotinylated horseradish peroxidase or avidin-biotinylated alkaline phosphatase complex. Antiserum to T alpha 1 stained the cell body, but not the processes, of GFAP-positive astrocytes, suggesting that T alpha 1 is a common antigen shared between thymus and astrocytes. Because T alpha 1 and its precursor molecule play a role in cell proliferation and immunomodulation, our findings could explain the role of astrocytes in certain central nervous system diseases.
Adult↗
Effect of GnRH agonists on the thymus in female rats.
The potential clinical applications of GnRH agonists are growing. We studied the effects of two GnRH agonists on the adult female rat thymus in 4 experiments. GnRH agonists administered sc and continuously significantly increased wet and dry thymic weights (absolute and relative). Thymic enlargement was related to the duration of treatment with GnRH agonists. The maximum increase in thymic weight occurred at approximately 18 days following initiation of treatment with GnRH agonists. Thymic enlargement does not appear to involve enhanced mitotic activity as measured by incorporation of tritiated thymidine into thymic tissue and thymic DNA. Histologic examination and computer-assisted morphometric analysis of thymuses indicated an increase in cortex to medulla ratio most pronounced at 10 and 18 days of GnRH agonist treatment. No consistent increases in splenic weight or bone marrow cell counts were observed. Thymosin alpha-1 but not thymosin beta-4 increased in GnRH agonist-treated rats. Thymic weight correlated negatively with ovarian and uterine weights, relative adrenal weight, serum estradiol, LH, and positively with thymosin alpha-1. Exogenous estrogen administration reversed GnRH agonist-induced thymic weight increase. Whether GnRH agonists have direct thymic effects remains to be determined.
Animals↗
Defective in vitro gamma interferon production and elevated serum immunoreactive thymosin beta 4 levels in patients with inflammatory bowel disease.
Gamma interferon (IFN-gamma) production by peripheral blood mononuclear cells (PBM) was measured in 21 patients with Crohn's disease, in 15 patients with ulcerative colitis, in 12 patients with non-IBD gastrointestinal disease (disease control), and in 28 healthy controls. T-cell subset proportions and serum levels of thymosin alpha 1 and thymosin beta 4, two hormonelike thymic peptides, were also determined. No differences were seen in T-cell subset proportions in patients with Crohn's disease or ulcerative colitis when compared to healthy controls or to the disease-control group. In vitro IFN-gamma production was markedly decreased in Crohn's disease and in untreated, but not treated, patients with ulcerative colitis. Preincubation of PBM prior to the addition of inducer mitogen resulted in enhanced IFN-gamma production in patients with Crohn's disease or ulcerative colitis which significantly exceeded that seen either in healthy controls or in the disease-control group. Serum thymosin alpha 1 levels were comparable in all study groups; however, serum thymosin beta 4 concentrations were significantly higher in all patient groups than in the healthy controls. These results confirm a defective in vitro IFN-gamma production in patients with IBD which is apparently independent of endocrine thymus regulation.
Crohn Disease↗
Imparied lymphocyte proliferative response to mitogen in alcoholic patients. Absence of a relation to liver disease activity.
Concanavalin A-induced lymphocyte proliferation was studied in 25 patients with alcoholic hepatitis or compensated alcoholic cirrhosis. Nine alcoholics without evidence of liver disease were also evaluated. A nonlinear correlation equation, which was natural logarithmic, was applied to individual dose-response proliferation curves and permitted comparisons between patient groups and controls. The proliferative response in all patient groups was significantly lower when compared to healthy controls and was independent of the presence or absence of liver disease. This suggests that some changes in immune function observed in alcoholics may be linked to the direct effects of alcohol on the immune system rather than to the associated liver disease.
Alcoholism↗
Amniotic fluid thymosin alpha 1 levels increase during gestation.
Thymosin alpha 1 is one of several cytokines produced by the thymus that modulates immune function. The presence of elevated serum levels of thymosin alpha 1 in pregnant women and their newborns has suggested that this peptide may play a role in perinatal immunology. In this investigation, we used a microenzyme-linked immunosorbent assay to assay amniotic fluid for immunoreactive thymosin alpha 1 and found levels that were remarkably higher than newborn serum levels (P less than 10(-4]. The increase of thymosin alpha 1 in amniotic fluid with fetal age was natural logarithmic (r = 0.838, P less than 10(-6]. Thymosin alpha 1 in amniotic fluid may account for some of the immunologic properties of this medium.
Amniotic Fluid↗
Enzyme immunoassay measurement of thymosin beta 4 in human serum.
An enzyme immunoassay (EIA) for measurement of human serum thymosin beta 4 is described. Antiserum to synthetic thymosin beta 4, raised in rabbits, is incubated with a standard or serum. The unbound antibody in liquid-phase then binds with solid-phase thymosin beta 4. The EIA is both sensitive and accurate and is capable of detecting as little as 2.5 ng/ml thymosin beta 4 in serum. No cross-reactivity was observed with common serum proteins or other putative thymic hormones. High-performance liquid chromatography of serum samples reveals a single thymosin beta 4 peak that corresponds to the authentic thymosin beta 4 peak in the standard. Human serum levels range from 3 to 82 ng/ml in 142 healthy adult human volunteers. Newborn cord serum levels of thymosin beta 4 are lower than in adults.
Alkaline Phosphatase↗
Quantitative analysis of mitogen-stimulated cellular proliferation: effect of concanavalin A and thymosin interaction.
Studies of mitogen stimulated lymphocyte proliferation have shown that considerable variation exists in the magnitude of response to specific mitogens. No standard method has been devised which would permit comparisons of the non-linear proliferation response between groups. In this study a mathematical correlation between mitogen stimulation and cellular response is defined using concanavalin A as the mitogen. A logistic equation was derived by least sum of squares regression analysis. The dose response relationship of concanavalin A stimulated peripheral blood mononuclear cell proliferation was natural logarithmic. A computing program was designed to accomodate any calculation related to proliferation assays. The efficacy of this program and the adequacy of the equation were confirmed after they were tested in thymosin fraction 5 treated cellular proliferation experiments. This study demonstrates a quantitative method for the comparisons of immunological proliferation response among groups.
Algorithms↗
Enzyme immunoassay measurement of thymosin beta 4.
An enzyme immunoassay for the measurement of thymosin beta 4, a chemically characterized thymic polypeptide, is described. A limited amount of reagent antiserum to synthetic thymosin beta 4 is incubated with liquid-phase thymosin beta 4. Unbound antibody is then incubated with solid-phase thymosin beta 4. The method is specific, sensitive, highly reproducible and capable of detecting as little as 2.5 ng/ml of thymosin beta 4.
Animals↗
Maternal and fetal circulating levels of thymosin alpha 1 during parturition.
The thymus directs T-lymphocyte development and contributes to the maintenance of immune homeostasis, in part, through its production of peptides known as thymosins. In pregnancy, maternal serum levels of thymosin alpha 1 have been reported to be low at midgestation and to increase by term, suggesting that maternal levels represent fetal levels. To evaluate this further, we obtained maternal venous and newborn mixed cord blood from 90 pregnancies between 20 and 42 weeks of gestation at delivery. An ELISA was used for thymosin alpha 1 assay, and analysis was by paired t test and regression. Maternal and newborn levels were independent of gestational age, but an apparent association (r = 0.51) between the two was inconclusive. Maternal levels (1,207 +/- 947 pg/ml) tended to be higher than those of healthy adults (1,043 +/- 576 pg/ml). Mixed umbilical cord serum levels (1,466 +/- 940 pg/ml) were higher than maternal levels (P less than or equal to 0.005). Although maternal thymosin alpha 1 levels may reflect fetal levels, immunological perturbations related to parturition appear to influence both.
Adolescent↗
MicroELISA method for measurement of human serum thymosin alpha 1.
A microELISA for the estimation of human serum thymosin alpha 1 is described. In this assay, antibody to thymosin alpha 1 is pre-incubated with the standard or serum at 4 degrees C. Unbound antibody in the liquid-phase then binds with solid-phase thymosin alpha 1. The method is sufficiently sensitive for measuring serum levels of thymosin alpha 1 and highly reproducible. The serum levels measured with the microELISA are comparable to serum levels of thymosin alpha 1 determined by the previously described radioimmunoassay for thymosin alpha 1.
Antibody Specificity↗
Measurement of thymosin alpha 1 by disassociation microELISA.
A disassociation microELISA was devised for the estimation of thymosin alpha 1, a chemically characterized thymic polypeptide isolated from bovine thymosin fraction 5. Antiserum to synthetic thymosin alpha 1 was raised in rabbits. Thymosin alpha 1 in liquid phase competed with a solid-phase-bound thymosin alpha 1 for this highly specific antibody. The method is specific, sensitive, reproducible and capable of detecting as little as 100 pg/ml of thymosin alpha 1.
Animals↗
Increased thymic hormone responsive suppressor T lymphocyte function in chronic active hepatitis.
Mitogen-induced suppressor T lymphocyte function was evaluated in patients with chronic active hepatitis (CAH). The in vitro effect of the biological response modifier, thymosin fraction 5, on the suppressive activity of peripheral blood mononuclear cells (PBM) was also assessed. Suppressor cell activity was significantly decreased in patients with CAH when compared to controls (P less than 0.001). In the absence of the inducing mitogen, thymosin-treated PBM from both patients and controls promoted enhancement of tritiated thymidine uptake by cocultured allogeneic lymphocytes. When thymosin-treated mononuclear cells were mitogen-activated; patients, but not the controls, showed a marked increase in suppressor activity (P less than 0.001). These results indicate that the polypeptides contained in thymosin fraction 5 can promote a helper effect in patients and controls. Furthermore, PBM from patients with CAH contain a subset of lymphocytes that can express a suppressive function following thymosin treatment. We conclude that thymosin fraction 5 can promote an in vitro restoration of suppressor T cell function in patients with CAH.
Adolescent↗
The effect of thymic humoral factor on intracellular lymphocyte cyclic AMP in alcoholic liver disease.
Intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) in resting peripheral blood mononuclear cells (PBM) were determined in patients with alcoholic hepatitis (AH), with compensated alcoholic cirrhosis, in alcoholic subjects without liver disease and in healthy controls. The effect of thymic humoral factor (THF), a polypeptide extract of the thymus, on T lymphocyte cAMP levels was also evaluated. Only PBM from patients with AH had significantly lower resting levels of cAMP when compared to the controls. The net increase in cAMP levels induced with THF were comparable for all patient and control groups. These findings indicate the presence of an immune dysfunction in patients with AH.
Cyclic AMP↗
Thymosin modulation of regulatory T cell function.
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Adult↗
Duodenal ulcer, hepatic abscesses, and fatal hemobilia with Behcet's syndrome: a case report.
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Adult↗
In vitro synthesis of IgG by peripheral blood lymphocytes in chronic liver disease.
In vitro IgG synthesis by peripheral blood mononuclear cells (PBM) from patients with chronic liver disease (CLD) was studied. In addition, the effect of pokeweed mitogen (PWM), polyadenylic-polyuridylic acid complexes (poly A:U) and thymosin fraction 5 on IgG synthesis was determined. Unstimulated cultures of PBM from patients with chronic active hepatitis (CAH) and alcoholic cirrhosis (AC) synthesized significantly higher quantities of IgG than the controls. Moreover, there was a direct correlation between serum IgG concentrations and the quantity of newly synthesized IgG in these unstimulated cultures. PWM, poly A:U and thymosin each stimulated increased IgG synthesis in the controls. While neither poly A:U nor thymosin enhanced IgG synthesis in patients with CLD, PWM increased IgG synthesis in CAH but not AC. These results indicate that spontaneous in vitro B cell synthesis of IgG is enhanced in CLD and may reflect antigenic stimulation in vivo.
Adult↗