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Biomedical subjects

W H Adler

Publications and source records attributed to W H Adler.

At least 73 records · Page 4Linked to original sources
PubMed1987

Supplemental zinc (Zn2+) restores antibody formation in cultures of aged spleen cells. II. Effects on mediator production.

In vitro antibody production to T-dependent erythrocyte antigens is depressed as a function of age. Supplementation of antibody-forming cultures with the essential trace element zinc restores the capacity of cells from immunodepressed, aged mice to generate an antibody response. Zn2+ produces maximal enhancement of immune function when it is added to the cultures within the first 24 h. Supernatants obtained from cultures supplemented with zinc from 0-24 h contain soluble, nondialyzable factors which support enhanced antibody production in fresh cultures of cells from aged mice. Interleukin 2 levels in the supernatants from Zn2+-supplemented cultures were not increased. However, the levels of interleukin 1 were increased approximately 300% over nonsupplemented controls and these increases corresponded with the ability of the supernatants to support antibody formation. Further studies showed that, in addition to enhancing the production of interleukin 1, Zn2+ enhanced the ability of concanavalin A-activated T cells from aged mice to produce B cell stimulatory factor-1.

Aging↗
PubMed1987

Regulation of interleukin 2 and interleukin 2 receptor gene expression in human T cells: I. Effect of Ca2+-ionophore on phorbol myristate acetate co-stimulated cells.

Human peripheral blood T lymphocytes were treated with phorbol myristate acetate (PMA), an activator of protein kinase C (PKC) activity, and with the calcium ionophore A23187. The resulting accumulation of specific mRNA for interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R), as well as IL-2 secretion and membrane IL-2R expression were examined. At low concentrations (0.1 microM), A23187 synergized maximally with PMA to induce proliferation, to increase IL-2R mRNA levels and the expression of membrane IL-2R, and to produce a low but sufficient accumulation of IL-2 mRNA and IL-2 secretion. A high concentration of A23187 (1.0 microM) did not show any synergism for the accumulation of IL-2R mRNA, membrane IL-2R expression and inhibited the proliferation of PMA co-stimulated T cells. It did, however, induce maximum accumulation of IL-2 mRNA and IL-2 secretion.

Calcimycin↗
PubMed1987

Impaired phorbol ester and calcium ionophore induced proliferation of T cells from old humans.

Current models of T cell activation implicate increases in intracellular free Ca2+ concentration and activation of the Ca2+ and phospholipid dependent enzyme protein kinase C (PKC) as important early events leading to interleukin 2 (IL-2) production, interleukin 2 receptor (IL-2R) expression, and subsequent cell proliferation. The present study examined the age-related defect in T cell proliferation to determine if signals that activate PKC and increase intracytosolic free Ca2+ concentration might be defective. Using phorbol myristate acetate (PMA), which directly activates PKC, and Ca2+ ionophore A23187, which increases intracellular cytoplasmic free Ca2+ concentration, the induction of IL-2 secretion, IL-2R expression and cell proliferation were studied. The results demonstrate that following stimulation with PMA and A23187, purified T cells from elderly subjects demonstrate low levels of IL-2 production, IL-2R expression and cell proliferation. Exogenous purified human IL-2 did not fully correct the low proliferative responses of T cells from old donors, however, did markedly boost the response. While it appears that the inability of T cells to express IL-2R and respond to IL-2, along with a lower endogenous IL-2 production are limiting factors in cell proliferation, the inability of PMA and A23187 to correct this defect suggests that the early phases of signal transduction per se are probably not a primary cause of the immunodeficiency seen in ageing.

Adult↗
PubMed1986

Age differences in phagocytosis by polymorphonuclear leukocytes measured by flow cytometry.

Elderly persons have increased morbidity and mortality due to bacterial infections. Since the polymorphonuclear leukocyte (PMN) is a major defense against bacterial infection, we utilized fluorescent microspheres and flow cytometry to examine phagocytosis by PMNs from 55 young and middle-aged adults (mean age 41.5 yrs) and two groups of elderly subjects: one group of 35 healthy individuals (mean age 74.1 years) living at home, and a second group of 11 residents (mean age 83.1 years) with severe mental and physical disabilities, living in a domiciliary care facility. We determined the percent phagocytic PMNs, the number of microspheres per PMN, and the number of microspheres per 100 PMNs. The mean number of microspheres per phagocytic PMN was similar for all groups. Statistically significant differences were found between the young and middle-aged group and the healthy or ill elderly groups for the percent phagocytic PMNs (75.3% vs 51.5% and 43.8%), and the number of microspheres per 100 phagocytic PMNs (197.3 vs 131.4 and 103.2). There were no significant differences in these parameters between healthy and debilitated elderly subjects. These data document that there is an age-related increase in representation of a population of PMNs which have a defect in phagocytic ability.

Adult↗
PubMed1986

Absolute peripheral blood lymphocyte count and subsequent mortality of elderly men. The Baltimore Longitudinal Study of Aging.

In this 16-year longitudinal study of 105 healthy elderly men, we analyzed one aspect of immunosenescence--a decline in the absolute number of peripheral blood lymphocytes--with particular reference to its relationship with subsequent mortality. It was found that there was a significantly (P less than .01) lower absolute lymphocyte count (1432 +/- 55/mm3; mean +/- SEM) within three years of death when compared with five years (1719 +/- 89/mm3) or 10 years (1715 +/- 98/mm3) before death. There was no relationship between this decrease in lymphocytes and age at death, smoking status, or prior cardiac illness. Previous cross-sectional studies have yielded conflicting data on age-related decreases in lymphocytes which may have been the result of an unrecognized selection process that either eliminated or included subjects who were close to death.

Aged↗
PubMed1986

Phenotypic expression of natural killer cell associated membrane antigens and cytolytic function of peripheral blood cells from different aged humans.

The function and phenotypes of peripheral blood NK cells from different aged adults were examined using a 4 hr 51Cr release NK assay and laser flow cytometry utilizing the Leu-7 and Leu-11 monoclonal antibodies. It was found that there was no difference between aged and young adults in the expression of Leu-7+, Leu-11+, Leu-7-11+ or Leu-7+11+ cells. A significant decrease, however, was seen in both percent representation and absolute number of Leu-7+11- cells in older subjects. When examined by age and gender, women aged 17-59 yr had a significantly lower percent representation and absolute number of Leu-11+, Leu-7-11+ and Leu-7+11+ cells and baseline NK activity than did men of similar age. No differences were seen between men and women aged 60-84 yr. No differences were seen in the degree of augmentation by interleukin-2 of NK function in any group. Our data indicate that NK function is correlated with cells bearing the Leu-11 surface antigen and that the gender of the cell donor is a significant factor in the representation of NK cells and function in persons under 60 yr of age. Studies on age differences in NK number and function must therefore take into account the percent of women in the populations studied.

Adolescent↗
PubMed1985

Epstein-Barr virus infection in a child with acquired immunodeficiency syndrome.

A 3-year-old girl, born to an intravenous-drug-dependent mother, had protracted diarrhea, failure to thrive, generalized lymphadenopathy, and recurrent fevers during the first six months of life. At 7 months of age, the Epstein-Barr virus (EBV) genome was detected in her saliva by DNA dot-blot hybridization using a cloned EBV probe. Spontaneous EBV+ lymphoblastoid cell lines had repeatedly developed from her peripheral blood lymphocytes over the subsequent 2 1/2 years. At 11 months of age, persistent tachypnea and a diffuse pulmonary infiltrate developed. Lung biopsy demonstrated a florid, peribronchiolar lymphocytic infiltrate and the EBV genome was identified in the lung tissue. Serum anti-EBV antibodies remained undetectable until 14 months of age. She had a T4+/T8+ ratio of less than 0.8 and serum antibody to human T-cell lymphotropic virus type III. The delayed seroresponse of this patient to symptomatic EBV infection suggests that reliance on EBV serology to diagnose EBV infection in immunocompromised hosts may be inappropriate, and other methods such as DNA probes should be used.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Analysis of immune status of hemodialyzed adults: association with prior transfusions.

Peripheral blood leukocytes of 29 hemodialyzed adults, 19 transfused and 10 nontransfused, were studied using immunofluorescent staining with monoclonal antibodies and in vitro measurement of natural killer (NK) cell activity. When compared with control subjects, the absolute number of leukocytes in transfused hemodialyzed patients was significantly reduced (P less than 0.01), as were the absolute numbers of OKT11+ cells (P less than 0.01), and OKT4+ cells (P less than 0.0001). The percent representation of OKT11+ and OKT4+ cells was also significantly lower among transfused hemodialyzed patients (P less than 0.01 and 0.001, respectively), and this loss of OKT4+ cells resulted in a decrease in the ratio of OKT4+/OKT8+ cells (P less than 0.01). The absolute number of Leu-7+ cells was also decreased in the transfused group (P less than 0.05). A decrease in in vitro NK cell activity was present in both transfused and nontransfused hemodialyzed subjects. Whether these differences in peripheral blood lymphocytes were induced by the erythrocyte transfusions could not be determined; however, if they reflect changes in central lymphoid tissues, then these results may help explain the prolonged survival of renal allografts in transfused individuals.

Adult↗
PubMed1984

Effect of feeding a diet with half of the recommended levels of all vitamins on the natural and inducible levels of cytotoxic activity in mouse spleen cells.

Groups of 6-week-old female C57Bl/6 mice were fed a normal diet with recommended levels of all vitamins or a vitamin-deficient (VD) diet containing half of the recommended level of each vitamin. At different time periods (1-11 weeks) after the initiation of diets, basal natural killer (NK) activity, interleukin-2 (IL-2) and concanavalin A (Con A)-induced cytotoxic activity, Con A-induced IL-2 production and levels of allospecific cytotoxic T cell activity generated in a mixed lymphocyte culture (MLC), were studied in spleen cells derived from control and VD mice. Results indicated that: (i) spleen NK activity remained normal until 2 weeks after the initiation of VD diet, fell steeply to low levels at the 4 and 5 week time points and remained depressed thereafter; (ii) IL-2- and Con A-induced levels of cytotoxic activity in spleen cells derived from VD mice declined at 4 weeks after the institution of VD diet, and then remained low throughout the study; (iii) the capacity of spleen cells from VD mice to generate IL-2 in response to Con A and cytotoxic T cells in response to allogeneic spleen cells, was normal at 1 and 4 weeks after initiation of the VD diet and was markedly depressed at the 6 and 9 week time points. These results suggest that partial combined deficiencies of dietary vitamins strongly influence assays of immune function.

Animals↗
PubMed1984

Effect of protein calorie malnutrition on the levels of natural and inducible cytotoxic activities in mouse spleen cells.

Six-week-old C57B1/6 female mice were fed a normal (24% protein) or an isocaloric but protein-deficient (4% protein) diet. At different time periods after the initiation of diets, basal natural killer (NK) activity, interleukin-2 (IL-2) and concanavalin-A (Con-A)-induced cytotoxic activity, Con-A-induced IL-2 production and levels of allospecific cytotoxic T cell activity generated in a mixed lymphocyte culture (MLC), were studied in spleen cells derived from control and protein deficient (PD) mice. Results indicated that (a) levels of spleen NK activity increased initially in PD mice, but after 7 weeks on PD diet declined to normal and subnormal levels, (b) IL-2 generation in response to Con-A as well as IL-2 activation of NK activity were comparable in spleen cells of control and PD mice at all time points tested, (c) Con-A-induced cytotoxic activity was significantly greater in spleen cells from PD mice, the difference being greater at higher doses of Con-A, and (d) generation of alloimmune cytotoxic T cells in a MLC reaction was normal in PD mouse spleen cells until 4 weeks after the beginning of PD diet, but declined markedly thereafter. Relevance of these observations to other related findings in protein calorie malnutrition are discussed.

Animals↗
PubMed1984

Supplemental zinc restores antibody formation in cultures of aged spleen cells.

The in vitro production of antibody to T-dependent antigens is depressed as a function of age. The addition of supplemental zinc to cultures of cells from young adult, middle-aged, and immunodepressed-aged mice enhances antibody production. The responses of young mice are enhanced 30 to 40%, but the responses in cultures from aged mice are increased 5- to 12-fold and the maximum response achieved is often equivalent to that of young, fully competent mice. The addition of zinc at varying times during the culture period suggests that zinc affects early events in the activation of antibody-forming cells.

Aging↗
PubMed1984

Interleukin-2-induced activation of natural killer activity in spleen cells from old and young mice.

Generation of natural killer (NK) activity in response to a partially purified preparation of rat interleukin-2 (IL-2) was compared in spleen cells derived from young (8-10 weeks old) and old (greater than 2 years old) female C57BL/6 mice. Significant NK activation was observed in both young and old mouse spleen cells incubated with 100 U IL-2/ml for 1-4 days, but the levels of cytotoxic activity generated in old mouse spleen cells was always lower than those of similarly treated young mouse spleen cells. Differences in IL-2-induced NK activation in old and young mouse spleen cells was obtained irrespective of the concentration of IL-2 used (25-400 U/ml). Quantitative comparisons indicated that old spleen cells activated by 3 day incubation with IL-2 acquired about two-fold higher NK activity than fresh young mouse spleen cells but still had only one-fourth of the levels of NK activity attained by IL-2-activated young mouse spleen cells. Cytotoxic activity of IL-2-activated young or old mouse spleen cells were totally abrogated by anti-asialo GM-1 antiserum + C but not by anti-Ly-2 + C treatment, indicating that the activated cytotoxic cells fell in the NK cell category. An analysis of NK precursor (NK-p) frequency by limiting dilution assay indicated that the NK-p frequency was about 4-fold higher in young as compared to old mouse spleen cells. The level of cytotoxic activity attained per NK-p cell was not significantly different for NK-p cells of old or young mice.

Aging↗
PubMed1983

Monoclonal antibody analysis of T-lymphocyte subsets in young and aged adults.

Eleven monoclonal antibodies identifying surface antigens present on human T lymphocytes were utilized to investigate the effects of advanced age on peripheral blood lymphocyte subsets. Both the proportion and number of lymphocytes recognized by five antibodies reactive with 'pan' T cell antigens (OKT3, OKT11, Leu4, T101 and Lyt3) decreased with age. The percentage of helper/inducer (OKT4+, Leu3a+) cells remained constant; however the proportion of Leu2a+, suppressor/cytotoxic cells declined. There was no change with age in the percent representation of OKT9+ or OKT10+ cells, nor in the ratio of helper/inducer to suppressor/cytotoxic cells (OKT4+/OKT8+ or Leu3a+/Leu2a+). Absolute numbers of helper/inducer (OKT4+, Leu3a+), suppressor/cytotoxic (OKT8+, Leu2a+), OKT9+ and OKT10+ cells were lower in elderly individuals as the result of lymphocytes constituting a lower percentage of the peripheral blood white cell population in this age group. While only small differences existed between the lymphocyte populations of young and aged men; aged women, compared to young women, had more dramatic shifts in their T cell populations. Comparison of antibodies putatively identifying similar (the same) functional groups of T cells demonstrated excellent correlation between the percentage of cells enumerated with the antibodies OKT3+: Leu4+ (r = .951), OKT4+: Leu3a+ (r = .914), OKT8+: Leu2a+ (r = .896), and in the ratio of helper/inducer to cytotoxic/suppressor OKT4+/OKT8+: Leu3a+/Leu2a+ (r = .926) cells.

Adult↗
PubMed1983

Human B cell function in responder and non-responder individuals. II. The role of T helper cells in promoting the PWM-induced B cell production of immunoprotein.

Sorted OKT4+ cells treated with pokeweed mitogen (PWM) and subsequently X-irradiated were used as a source of helper T cells to examine human T and B cell function. PWM-induced immunoprotein synthesis by human peripheral blood lymphocytes was the model used to study the cellular interactions. PWM was shown to induce helper T cell function which caused non-PWM treated B cells to secrete immunoglobulin. PBL from certain individuals could not be induced by PWM to secrete Ig therefore allogeneic co-cultures of helper T cells and B cells were examined to define the defective cell population. Ig synthesis in allogeneic cultures of T and B cells was always greater than that observed in autologous cultures when cells from responders were assayed. However, when allogeneic cultures were initiated using B cells from a responder and PWM treated T cells from a non-responder and examined for Ig synthesis, the B cell responses were markedly lower than seen in the autologous responder cultures. In addition, PWM activated helper T cells from a responder induced a significantly higher Ig synthesis by B cells from a non-responder. These observations indicate that PBL from individuals who do not respond in a PWM driven Ig synthesis assay have relatively normal B cell function but are deficient in helper T cell function.

Antibodies, Monoclonal↗
PubMed1983

Direct antiproliferative effects of cyclosporin A on murine lymphoreticular tumor cells in culture.

Cyclosporin A (CSA) has been shown to prevent mouse spleen cell blast formation in response to concanavalin A (con A) and to inhibit lymphocyte proliferation. In the presence of interleukin-2 (IL-2), however, the proliferation of preformed blasts is not affected by CSA. We examined the effects of CSA on the growth in culture of several established mouse lymphoreticular tumor-cell lines proliferating independently of exogenous lymphokines. We found that CSA abolished, by direct cytolysis, growth of the T-lymphoma lines, EL4, WEHI22.1, S49.1, RL male 1, WR19L, and YAC. In contrast, growth of the non T-cell lines, S49, P388D1, RAW264.7, PU51.R, P815, P3X63Ag8, and L929, was variably retarded by a noncytocidal action of CSA. The concentration of CSA required for T-cell cytolysis was relatively high and directly related to the numbers of cells treated. Expression of Thy-1 antigen predicted for the susceptibility of a cell line to CSA-induced lysis. At the concentrations used there was no evidence of significant mitotic death following CSA treatment; cells previously exposed to CSA and then washed were able to resume a delayed but otherwise normal pattern of replication. In a preliminary experiment, CSA afforded significant protection to C57BL/6 mice transplanted with syngeneic EL4 cells. The results indicate that CSA, in vitro and in vivo, is a potent antiproliferative agent selective for T cells, and that in the absence of growth factors its inhibitory effects are not limited to early event(s) in the T-cell activation process.

Animals↗