Long-acting bronchodilators for the control of asthma symptoms.
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Adrenergic beta-2 Receptor Agonists↗
Biomedical subjects
G D Marshall
Publications and source records attributed to G D Marshall.
Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines.
Glucocorticoids, at concentrations mimicking stress-physiologic plasma levels, cause an in vitro shift in the type 1/type 2 cytokine balance of human peripheral blood mononuclear cells (PBMC) toward a predominant type 2 response. The mechanisms of these immune alterations are currently unknown but may involve modulation of key cytokines known to regulate the type 1/type 2 cytokine balance. Therefore, we sought to determine the role of cytokines previously reported to regulate the type 1/type 2 cytokine balance, including interleukin-12 (IL-12), interferon-gamma (IFN-gamma, IL-10, IL-4, and IL-13, in the glucocorticoid-mediated human type 1/type 2 cytokine alterations. Human PBMC were stimulated in vitro with tetanus toxoid in the presence of 10(-8) M dexamethasone (DEX). Cultures were supplemented with recombinant human (rHuIL-12), rHuIFN-gamma, or neutralizing monoclonal antibodies (mAb) against IL-4, IL-10, or IL-13. DEX decreased IFN-gamma production and increased IL-4 and IL-10 production by tetanus-stimulated PBMC. The addition of either recombinant IL-12p70 or IFN-gamma abrogated the DEX-mediated decrease in IFN-gamma and increase in IL-4 production. Neutralization of IL-4 activity partially abrogated the DEX-induced alterations in IFN-gamma and IL-4, but not IL-10, production. Neutralization of IL-10 or IL-13 had no effect on the Dex-mediated type 1/type 2 cytokine alterations. Therefore, the DEX-mediated type 1/type 2 cytokine alterations in tetanus-stimulated PBMC are primarily the result of downregulation of type 1 cytokines, subsequently permitting the production of type 2 cytokines.
Adult↗
Increased fecal IgE among infants in a rural community of Egypt: an analysis of associated risk factors.
Newborns in rural Bilbeis, Egypt were followed to 1-year of age to document the incidence and risk factors associated with the development of fecal IgE. Factors associated with increased fecal IgE included infants aged 3-6 months (relative risk (RR) = 3.28, 95 per cent confidence intervals (CI) = 1.03-13.60, p < 0.05) and mother being vaccinated antenatally (RR = 2.17, CI - 1.01-4.61, p < 0.05). Decreased fecal IgE was observed with consumption of rice (RR = 0.37, CI = 0.12-0.94, p < 0.05), biscuits (RR = 0.43, CI = 0.15-0.99, p < 0.05), potatoes (RR = 0.39, CI = 0.11-0.98, p < 0.05), and fruits and vegetables (RR = 0.20, CI = 0.02-0.80, p < 0.05). After multivariate adjustment, increased risk was observed with consumption of milk pudding (RR = 7.48, CI = 1.54-36.20, p < 0.05) and wet-nursed infants (RR = 2.77, CI = 1.17-6.54, p < 0.05). Infants who were completely breastfed (RR = 0.13, CI = 0.02-0.68, p < 0.05) and infants' family owning a television set (RR = 0.29, CI = 0.12-0.67, p < 0.05) were less likely to develop fecal IgE. Our findings indicate that prelacteal feeding with certain foods, early supplementation of breastfeeding, and sociodemographic factors are associated with increased fecal IgE.
Analysis of Variance↗
Stress effects on immunity and its application to clinical immunology.
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Humans↗
Silica and PM1648 modify human alveolar macrophage antigen-presenting cell activity in vitro.
Some inhaled particles are known to lead to inflammation and lung pathology, whereas others do not appear to have long-term effects. Potential mechanisms to account for these differences are only beginning to be understood. In this article we examine whether silica and PM1648 (a model urban particulate) caused selective deletion of the suppressor human alveolar macrophage (HAM) phenotype (RFD1+/7+), and whether this affected cytokine production in an antigen-presenting cell (APC) assay with autologous T lymphocytes. HAM were exposed to the bioactive particulates, silica and PM1648, for 24 hours, then isolated free of extracellular particulates and nonviable cells; HAM were then cultured with autologous lymphocytes in an 11-day APC assay. Silica exposure up-regulated a TH1 lymphocyte-derived cytokine, interferon gamma (IFN-gamma), and a TH2 lymphocyte-derived cytokine, interleukin-4 (IL-4). PM1648 exposure primarily upregulated IL-4. Neither particle exposure had a significant effect on interleukin-10 (IL-10) production. Control particulate exposures with titanium dioxide (TiO2) and wollastonite (Woll) caused no altered APC activity. Silica and PM1648 demonstrated selective toxicity to suppressor macrophages (RFD1+/7+). We propose that, because of the suppressor macrophage phenotype disabling, the activator macrophage (RFD1+/7-) operates free of the suppressor macrophage's influence, enhancing APC activity with increased lymphocyte-derived proinflammatory cytokine production.
Air Pollutants, Occupational↗
Beta-adrenergic modulation of human type-1/type-2 cytokine balance.
BACKGROUND: Neuroendocrine mediators are increasingly recognized as immunomodulatory agents. Lymphocytes and monocytes express receptors for a variety of neuroendocrine mediators, including catecholamines. It has been reported that beta-adrenergic agonists decrease IFN-gamma production, with varying effects on IL-4 and IL-5 production. OBJECTIVE: Our purpose was to determine the effects of catecholamines (including beta-adrenergic agonists) on the type-1/type-2 cytokine balance in tetanus-stimulated human PBMCs. METHOD: Human PBMCs were stimulated with tetanus in the presence of epinephrine (EPI), norepinephrine, or terbutaline. IFN-gamma, IL-4, IL-5, and IL-10 levels in the supernatants were determined by ELISA. RESULTS: PBMCs stimulated in the presence of EPI produced decreased levels of IFN-gamma and increased levels of IL-10, IL-4, and IL-5. A small decrease in IFN-gamma production and an increase in IL-10, IL-4, and IL-5 production were also observed with norepinephrine. Terbutaline induced similar alterations in the type-1/type-2 cytokine balance compared with EPI, indicating that the beta(2)adrenergic receptor is involved in these cytokine alterations. Furthermore, these cytokine alterations were blocked by propranolol. Finally, IL-12p70 prevented the cytokine alterations, suggesting that the mechanism of beta-adrenergic-induced cytokine alterations involves a decrease in IL-12. CONCLUSION: beta-Adrenergic agonists induce a shift in the human type-1/type-2 cytokine balance toward a type-2 response. These data provide a potential mechanism to explain the paradoxical increase in asthma morbidity and mortality associated with the chronic use of scheduled dosing of short-acting beta-adrenergic agonists.
Adrenergic alpha-Agonists↗
DNA repair capacity in healthy medical students during and after exam stress.
There has been extensive research into the effects of stress on immune function but little on the effects of stress on DNA repair capacity (DRC), a process central to maintaining a normal cell cycle. Defective DRC is one of the factors responsible for carcinogenesis. In the present study we assessed DRC in healthy medical students during times of high and low stress. Sixteen medical students were evaluated during the third day of a 5-day exam period and then again 3 weeks later, after vacation. At both time points, participants underwent a brief physical examination, had venous blood drawn, and completed questionnaires to identify subjective stress levels. The DRC was assessed by the host-cell reaction assay, which measures nucleotide excision repair capacity. Participants reported significantly higher levels of subjective stress during the exam period than after vacation. DRC was also significantly higher during the exam period than after vacation, suggesting a positive association between subject stress levels and DRC. The results are discussed in relation to previous findings and implications for cancer research.
Adult↗
Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents.
As has been reported throughout this supplement, the pathophysiologic factors of allergic diseases involve many elements of systemic disease-effector-cell recruitment from circulation, stimulation of bone marrow progenitors, systemic effector-cell priming, anaphylactic reactions, and others. With this understanding, allergic inflammation can be thought of as a reflection of systemic immunologic responses with compartmentalized manifestations in various organ systems, including the upper respiratory tract, lungs, gastrointestinal tract, and skin. Thus, any therapeutic approach to the treatment of allergic disease should address, in addition to the localized disease manifestations, the systemic immunologic dysregulation. Second-generation antihistamines (cetirizine, fexofenadine, loratadine) have been used since the 1980s to treat localized allergy symptoms in upper airways, skin, and, in some cases, the lungs; however, the efficacy of these agents in controlling systemic immune dysregulation and chronic allergic inflammation (eg, nasal congestion) has not been proved. The potential role of newer antihistamines in the amelioration of both localized and systemic aspects of allergic disease represents an active area of interest. Desloratadine, a new selective histamine H(1)-receptor antagonist with potent antihistaminic and anti-inflammatory activity, is introduced and its potential for treating the systemic aspects of allergic disease is discussed.
Anti-Allergic Agents↗
Role of CD28/B7 costimulation in the dexamethasone-induced suppression of IFN-gamma.
In vitro exposure of peripheral blood mononuclear cells (PBMC) to glucocorticoids (GC), at concentrations observed during psychologic stress, induces a shift in the human type 1/type 2 cytokine balance toward a type 2 cytokine response. The mechanisms involved in these cytokine alterations are unknown but likely include modulation of regulatory cytokines or the interaction between the antigen-presenting cell (APC) and T lymphocyte or both. The CD28/B7 costimulation pathway has been reported to modulate the type 1/type 2 cytokine balance and may contribute to the GC-associated cytokine alterations. Therefore, we sought to determine the effect of dexamethasone (Dex) on the expression and function of the human CD28/B7 costimulatory pathway and whether these alterations contribute to the Dex-induced type 1/type 2 cytokine alterations. Dex inhibited the expression of both CD80 and CD86 on THP-1 cells, a human acute monocytic leukemia cell line, as determined by flow cytometry. Dex also inhibited the expression of CD28 and CTLA-4 on phytohemagglutinin (PHA)-stimulated CD3+ T lymphocytes, which was attenuated by the addition of interleukin-12 (IL-12). Lastly, activation of CD28 with anti-CD28 antibody attenuated the Dex-induced decrease in interferon-gamma (IFN-gamma) production by anti-CD3 antibody-stimulated PBMC. These data suggest that Dex induces a modulation of the CD28/B7 costimulatory pathway that contributes to the shift in the type 1/type 2 cytokine balance toward a predominant type 2 cytokine response.
Abatacept↗
Determining allergic versus nonallergic drug reactions.
Drug sensitivity is a major clinical problem that is incompletely understood. Much effort continues in identifying patients at risk for developing drug sensitivities, predicting the various immune mechanisms most likely to be activated by a specific drug, and developing more reliable tests to identify the drug-allergic patient.
Diagnosis, Differential↗
Perimenstrual alterations in type-1/type-2 cytokine balance of normal women.
BACKGROUND: Perturbations of the type-1/type-2 cytokine balance play a role in the pathogenesis of many diseases. Several immune-based diseases, such as asthma, have significant clinical exacerbations during specific intervals of the menstrual cycle and are associated with oral contraceptive pills (OCRs). The mechanism for these changes is not known, but may involve alterations in the type-1/type-2 cytokine balance. OBJECTIVE: To determine if the type-1/type-2 cytokine balance in healthy women changes during a regular menstrual cycle. METHODS: Peripheral blood mononuclear cells from 14 healthy women (seven taking monophasic OCPs) obtained during the perimenstrual interval (3 days prior to 4 days after the onset of menses) and the mid-cycle interval (days 13 to 16) were stimulated with PHA. Supernatants were analyzed for type-1 (IFN-gamma) and type-2 (IL-10) cytokines. RESULTS: During the perimenstrual interval PBMC produced less IFN-gamma and more IL-10, resulting in a decreased IFN-gamma: IL-10 ratio compared with the mid-cycle interval. The perimenstrual decrease in the IFN-gamma: IL-10 ratio was observed in women not taking OCP, but not in women taking OCP. Furthermore, the OCP group had a lower mid-cycle IFN-gamma: IL-10 ratio compared with the control group. Finally, subjects reported increased levels of distress during the perimenstrual interval compared with the mid-cycle interval. CONCLUSIONS: These data suggest that healthy women have a perimenstrual shift in the type-1/type-2 cytokine balance toward a type-2 response that is blunted in women taking OCP.
Adult↗
Cytokine dysregulation associated with exam stress in healthy medical students.
The mechanisms of stress-related immune alterations have not been fully elucidated. Cell-mediated immune responses as well as antibody and certain cytokines are reported as being suppressed during times of high stress. However, the role of suppression vs dysregulation has not been established in human stress models. The effect of exam stress on regulatory cytokines in 16 healthy medical students was assessed by measuring type-1 (IFN-gamma) and type-2 (IL-10) cytokines from 72-h PHA/PMA-stimulated PBMC 4 weeks before and 48 h after exams. Results demonstrated decreased IFN-gamma accompanied by increased IL-10 during exam stress that resulted in a decreased IFN-gamma:IL-10 ratio. There was a significant correlation between the cytokine response to PHA/PMA and number and subjective adjustment to daily hassles. Additionally, students who reported greater levels of loneliness also reported greater numbers of and poorer subjective adjustment to hassles. The differences were consistent in both males and females but did not correlate with AM cortisol levels. Additionally, when individuals were grouped into high vs low preexam hassle levels, the type-1/type-2 shift in the IFN-gamma:IL-10 ratio occurred in the low hassles group only. These data suggest that psychologically stressful situations shift type-1/type-2 cytokine balance toward type-2 and result in an immune dysregulation rather than overall immunosuppression. This may partially explain the increased incidence of type-2-mediated conditions such as increased viral infections, latent viral expression, allergic/asthmatic reactions, and autoimmunity reported during periods of high stress.
Adult↗
In vivo alteration in type-1 and type-2 cytokine balance: a possible mechanism for elevated total IgE in HIV-infected patients.
The progression of HIV infection has been associated with an increase in the plasma levels of total IgE. The mechanisms responsible for the increased IgE have not been elucidated. The type-1 and type-2 cytokine imbalance associated with HIV infection has been proposed as a possible mechanism for elevated IgE. The current study was undertaken to investigate the relationship between total IgE, type-1 and type-2 cytokines from a large HIV+ patient population. HIV+ patients were found to have elevated total IgE that inversely correlated with numbers of CD4+ T-cells. HIV+ plasma was also found to have decreased IFN-gamma and IL-12p70 levels as well as increased IL-10 levels compared to HIV-negative individuals. HIV+ patients with more advanced disease, as defined by absolute CD4+ counts, demonstrated more marked differences. Furthermore, the relative ratios of IFN-gamma:IL-10 and IL-12:IL-10 were decreased in HIV+ patients compared to HIV-negative individuals. The alterations in the plasma cytokines suggest a switch from a predominance of type-1 cytokines to type-2 cytokines that may enhance IgE synthesis. These data suggest that measurement of plasma IgE and/or cytokines may have prognostic or therapeutic monitoring value in HIV+ patients.
Adolescent↗
Glucocorticoid-induced type 1/type 2 cytokine alterations in humans: a model for stress-related immune dysfunction.
Increased psychologic and physiologic stressors can have profound effects on the immune system. Previously believed to be immunosuppressive, there is mounting evidence that stress may actually induce a shift in the type 1/type 2 cytokine balance toward a type 2 cytokine response. Cortisol is elevated in response to stress and has been reported to alter cytokine production in murine and human peripheral blood mononuclear cells (PBMC). The current investigation examined the effects of dexamethasone (DEX) mimicking basal, stress, and supraphysiologic levels of cortisol on production of interferon-gamma (IFN-gamma) (type-1), interleukin (IL)-12p40 (type 1), IL-10 (type 2), and IL-4 (type 2) by human PBMC. Both supraphysiologic and stress levels of DEX decreased production of type 1 cytokines and either increased or maintained production of type 2 cytokines PBMC stimulated with phytohemagglutinin (PHA), immobilized anti-CD3, lipopolysaccharide (LPS) or tetanus. Although preincubation with DEX was sufficient to induce a type 2 switch in short-term mitogen cultures, PBMC cultures for extended periods of time required DEX at the initiation and throughout the duration of culture. Mifepristone, a glucocorticoid receptor antagonist, blocked the DEX-induced shift in the type 1/type 2 cytokine balance. These data demonstrated the ability of the glucocorticoid dexamethasone, to induce a shift in the type 1/type 2 cytokine balance toward a type 2 cytokine response and simulate the type 1/type 2 cytokine alterations observed in in vivo stress models. This model will allow detailed investigation of the cellular and molecular mechanisms of stress-induced immune alterations in humans.
Adult↗
Distinct serum cytokines in AIDS-related skin diseases.
To determine whether common skin diseases associated with human immunodeficiency virus (HIV) were distinguishable based on the pattern of serum cytokine expression, we studied patients with psoriasis, pruritus, and Kaposi's sarcoma (KS) for levels of tumor necrosis factor (TNF)-alpha, interferon-gamma (IFN-y), interleukin (IL)-10, and IL-4. Thirty-two HIV-positive (HIV+) patients including 8 with KS, 11 with psoriasis, and 13 with pruritus along with 16 HIV-negative subjects with psoriasis were studied. IFN-gamma levels were highest in sera of HIV+ patients with psoriasis (p = 0.040). By contrast, TNF-alpha and IL-10 levels were highest in sera of HIV+ patients with pruritus (p = 0.012). Detectable levels of all cytokines in these patients were remarkably higher than for healthy adults. These results suggest that common skin diseases associated with HIV infection and AIDS can be distinguished by the production of unique cytokines.
Acquired Immunodeficiency Syndrome↗
Dusting off recombinant allergens.
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Allergens↗
Ingested IFN-alpha has biological effects in humans with relapsing-remitting multiple sclerosis.
Parenterally administered human recombinant type I interferons (hrIFN) in relapsing-remitting multiple sclerosis (RRMS) decrease relapses and spontaneous in vitro IFN-gamma production, reduce clinical progression, and decrease magnetic resonance imaging (MRI)-defined disease activity and lesions. Parenterally administered type I IFN use is limited by clinical and chemical toxicities, and the induction of antibodies that abrogate their activity in vivo correlated with the loss of clinical benefit. Therefore, we determined whether ingested IFN-alpha was non-toxic and had biological effects in humans. Ingested hrIFN-alpha showed no toxicity in normal volunteers or patients with RRMS at doses ranging from 300 to 100,000 units. In subjects with RRMS, a significant decrease in Con A-mediated proliferation and serum soluble intercellular adhesion molecule-1 (sICAM-1), a surrogate measure for disease activity in MS, was found after ingesting 10,000 and 30,000 units IFN-alpha The RRMS subjects also showed decreased IL-2 secretion after ingesting 10,000 units IFN-alpha and decreased IFN-gamma, TGF-beta and IL-10 production after ingesting 30,000 units IFN-alpha. The decreased secretion of IFN-gamma and IL-2 by ingested IFN-alpha suggests that oral IFN-alpha may cause a functional inhibition of Th J-like T helper cells in RRMS, a potential site of intervention at the level of effector T cells in MS. Our studies support the oral use of human IFN-alpha as a biological response modifier in humans.
Administration, Oral↗
Interferon-beta 1b treatment decreases tumor necrosis factor-alpha and increases interleukin-6 production in multiple sclerosis.
MS is presumed to be a T-cell-mediated chronic inflammatory disease of the CNS. We examined proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 [anti-CD3] monoclonal antibody (MAb) or concanavalin A (Con A) in subjects with stable relapsing-remitting MS (RR MS) before and after initiating interferon (IFN)-beta 1b treatment. There was no significant difference in pretreatment to on-treatment anti-CD3 mAb or Con A-induced proliferation in RR MS patients. There was significantly increased Con A-induced secretion of tumor necrosis factor (TNF)-alpha, IFN-gamma, interleukin (IL)-2, IL-6, and IL-10 and decreased IL-4 secretion in on-treatment compared with pretreatment peripheral blood mononuclear cell samples. However, on-treatment CD3-mediated secretion of TNF-alpha was significantly decreased, and IL-6 secretion was significantly increased compared with pretreatment values. IFN-gamma was also decreased in on-treatment cultures stimulated with anti-CD3 MAb, but these values did not reach statistical significance. Systemic side effects from IFN-beta 1b were associated with increased IL-6 secretion. There were no significant changes in CD3-mediated IL-4, IL-10, transforming growth factor (TGF)-beta, or IL-2 secretion or Con A-induced TGF-beta secretion. IFN-beta 1b (Betaseron) decreases CD3-mediated TNF-alpha secretion but increases another inflammatory cytokine, IL-6, that could potentially counteract its beneficial immunomodulatory effects.
Autoimmune Diseases↗