Title: Anti-Ige Therapy in Asthma: Rationale and Therapeutic Potential
Author: Barnes, P. J.; (Date: Nov, 2000)
Journal: Int Arch Allergy Immunol; V. 123; Issue: 3; Pages: 196-204
Abstract: Airway inflammation is found in virtually all individuals with asthma symptoms. The factors contributing to asthma-related airway inflammation are multiple and involve a number of different inflammatory cells and mediators. Allergic responses at the level of the respiratory system are mostly mediated by IgE-dependent mechanisms. After sensitization of a susceptible individual and the synthesis and binding of allergen-specific IgE to target cells, atopic individuals respond immunologically to common, naturally occurring allergens by releasing mast cell-derived mediators. Subsequent allergen exposure in susceptible individuals produces a characteristic cascade of events orchestrated by immune effector cells, most prominently, mast cells, T lymphocytes and eosinophils. A new strategy, neutralizing IgE antibodies, inhibits expression of allergic symptoms by preventing the initial trigger of the allergic reaction, IgE binding to IgE-receptor bearing cells. rhuMAb-E25 is a recombinant humanized monoclonal anti-IgE antibody currently under investigation that has been shown to reduce allergic responses in atopic individuals and to improve symptoms and reduce rescue medication and corticosteroid use in patients with allergic asthma. Thus, the clinical effectiveness of rhuMAb-E25 supports the central role of IgE in allergic reactions and the viability of anti-IgE therapy as a potentially effective treatment option for asthma.
Notes: Journal Article
Author Address: National Heart and Lung Institute, London, UK. firstname.lastname@example.org
Title: Corticosteroids Inhibit Il-12 Production in Human Monocytes and Enhance Their Capacity to Induce Il-4 Synthesis in Cd4+ Lymphocytes
Author: Blotta, M. H.; DeKruyff, R. H.; Umetsu, D. T.; (Date: Jun 15, 1997)
Journal: J Immunol; V. 158; Issue: 12; Pages: 5589-95
Abstract: We examined the effects of corticosteroids on IL-12 production by human monocytes and on cytokine synthesis in T cells. To distinguish the effects of corticosteroids on the APC used to activate the T cell from direct effects of corticosteroids on the T cell, experiments were performed by exposing the APC and not the T cell to corticosteroids. We found that corticosteroids significantly inhibited the production in monocytes of IL-12, a cytokine that is extremely potent in enhancing IFN-gamma and inhibiting IL-4 synthesis in T cells. We demonstrated that reduced production of IL-12 in corticosteroid-treated monocytes resulted in a decreased capacity of the monocytes to induce IFN-gamma and an increased ability to induce IL-4 in T cells. These results suggest that although corticosteroids may be beneficial for the treatment of asthma or allergic disease due to direct inhibitory effects of corticosteroids on cytokine synthesis in T cells, chronic corticosteroid therapy may indirectly exacerbate the long-term course of allergic disease. This deleterious effect of corticosteroids would result from a limitation in IL-12 production in tissue monocytes and macrophages, which would enhance production of Th2 cytokines (which augment allergic disease), and would reduce production of Th1 cytokines (which attenuate allergic disease) in T cells that subsequently infiltrate the tissues.
Notes: Journal Article
Author Address: Department of Pediatrics, Stanford University, CA 94305, USA.
Title: Premenstrual Asthma: The Effect of Estrogen on Symptoms, Pulmonary Function, and Beta 2-Receptors
Author: Chandler, M. H.; Schuldheisz, S.; Phillips, B. A.; Muse, K. N.; (Date: Mar-Apr, 1997)
Journal: Pharmacotherapy; V. 17; Issue: 2; Pages: 224-34
Abstract: STUDY OBJECTIVES: To characterize asthma symptoms, pulmonary function, and responsiveness to beta 2-agonist stimulation, and in vitro beta 2-receptor density and cyclic adenosine 3′,5′-monophosphate (cAMP) response throughout the menstrual cycle in women with premenstrual asthma (PMA); and to examine the effect of exogenous estradiol administration on asthma symptoms, pulmonary function and responsiveness, and beta 2-receptor density and function in these women. DESIGN: Open-label, longitudinal, 9-week study. SETTING: A university clinical research center. PATIENTS: Seventeen women with mild to moderate asthma, of whom 14 completed the study. INTERVENTIONS: Every morning on awakening during the entire 9-week study, each subject completed visual analog scales for asthma symptomatology (cough, wheezing, breathlessness, chest tightness) and measured and recorded her peak expiratory flow rate (PEFR) with a peak flow meter. Also measured at various times throughout the menstrual cycle were dyspnea index scores, pulmonary function (PEFR, forced expiratory volume in 1 sec [FEV1]), pulmonary response to subcutaneous terbutaline, T lymphocyte beta 2-receptor density (Bmax) and function (cAMP), and estradiol, progesterone, and catecholamine concentrations, both with and without exogenous estradiol administration. MEASUREMENTS AND MAIN RESULTS: At the time of enrollment, only 5 subjects reported premenstrual worsening of asthma symptoms, but all 14 had greater than 20% decrease in PEFR and/or increase in symptoms premenstrually during the study. Significant differences (p < 0.05) existed in asthma symptoms and PEFR between day 13 (highest estradiol concentrations) and day 26 (lowest estradiol concentrations) of the menstrual cycle. Asthma symptoms and dyspnea index scores were significantly improved (p < 0.05) after estradiol administration compared with baseline (premenstrual period without exogenous estrogen). Pulmonary response to terbutaline, beta 2-receptor density and function, and catecholamine concentrations were not significantly altered after estradiol administration, but the trend was toward significant differences (0.05 < p < 0.2) in pulmonary function tests (PEFR, FEV1). CONCLUSIONS: Even asthmatics not previously aware of PMA may experience premenstrual worsening of asthma symptoms and/or PEFR. Estradiol is associated with a significant improvement in asthma symptoms and dyspnea index scores. This ameliorating effect does not appear to be related to beta 2-receptors.
Notes: Clinical Trial
Author Address: Division of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, USA.
Title: Regular Inhaled Salbutamol and Airway Responsiveness to Allergen
Author: Cockcroft, D. W.; McParland, C. P.; Britto, S. A.; Swystun, V. A.; Rutherford, B. C.; (Date: Oct 2, 1993)
Journal: Lancet; V. 342; Issue: 8875; Pages: 833-7
Abstract: Regular inhaled beta 2 agonist causes tolerance to the acute protective effect of beta 2 agonist against bronchoconstriction induced by chemical stimuli such as AMP, histamine, and methacholine. We examined a more clinically relevant stimulus, inhaled allergen, in a double-blind, cross-over, random-order trial in 13 mild atopic asthmatics, who had not used beta 2 agonist for at least 4 weeks. We compared regular inhaled salbutamol (200 micrograms four times daily for 2 weeks) with placebo (2 weeks) for effects on bronchodilator response, baseline methacholine, and allergen airway responsiveness, and on the acute protective effect of salbutamol against both stimuli. Baseline forced expiratory volume in 1 s (FEV1), bronchodilator response, and methacholine responsiveness were the same during both treatment periods. After regular salbutamol, the allergen PC20 (provocation concentration producing a 20% FEV1 decrease) fell by 0.91 (SD 0.66) (p = 0.0009) doubling doses, and the protective effects of salbutamol on methacholine and allergen were both significantly reduced (p = 0.026 and 0.025, respectively). Taking into account the reduced baseline allergen PC20, the post-salbutamol allergen PC20 was almost 2 doubling doses (1.94 [1.43], p < 0.01) lower during salbutamol treatment. Thus, 2 weeks of regular inhaled salbutamol increased airway responsiveness to allergen but not to methacholine, and caused tolerance to the protective effect of salbutamol on bronchoconstriction induced by both stimuli. These effects of inhaled beta 2 agonist provide further evidence to support detrimental effects of their regular use.
Notes: Clinical Trial
Randomized Controlled Trial
Author Address: Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Canada.
Abstract: Diuretic agents influence the renal handling of magnesium, causing increased losses of the ion. Continuing magnesium losses may, in the long term, result in a magnesium deficiency. 296 patients with congestive heart failure or arterial hypertension receiving long term diuretic therapy were studied by skeletal muscle biopsies to assess their magnesium status. 65% of the congestive heart failure patients and 42% of the patients with arterial hypertension were found to have subnormal values for skeletal muscle magnesium. Studies with the potassium-sparing diuretics amiloride, spironolactone and triamterene demonstrate that these drugs significantly increase the muscle magnesium content in patients on long term diuretic treatment for congestive heart failure and/or arterial hypertension–in addition to their well known positive effect on potassium balance.
Notes: Journal Article
Title: Bone Mineral Density and Bone Turnover in Asthmatics Treated with Long-Term Inhaled or Oral Glucocorticoids
Author: Ebeling, P. R.; Erbas, B.; Hopper, J. L.; Wark, J. D.; Rubinfeld, A. R.; (Date: Aug, 1998)
Journal: J Bone Miner Res; V. 13; Issue: 8; Pages: 1283-9
Abstract: Inhaled glucocorticoids are pivotal in maintenance therapy of chronic bronchial asthma; however, conflict exists over their effects on bone and mineral metabolism. We measured bone mineral density (BMD), bone turnover markers, and adrenal steroid hormones in 53 patients (34 female, 19 male) with chronic bronchial asthma who had taken either inhaled beclomethasone or budesonide in doses of > or = 1500 microg/day for at least 12 months to determine pathogenetic mechanisms of bone loss. To account for the effect of prior oral glucocorticoid exposure we divided patients into two groups: one with (OG) and the other without (IG) a past history of maintenance (> 1 month) oral glucocorticoid therapy. Lumbar spine (LS) and proximal femur BMDs were approximately 1 SD lower in men and women taking OG or high-dose IG for chronic bronchial asthma, potentially equivalent to a doubling of the risk of fracture at these sites. Prior exposure to OG in women was also associated with lower LS and proximal femur BMDs, while men were more sensitive to the adverse effects of IG on LS and Ward’s triangle BMDs. Bone formation markers were decreased; however, bone resorption marker concentrations were normal. All patients had evidence of suppression of both endogenous glucocorticoid and adrenal androgen production. Both total duration of OG and biochemical bone turnover marker concentrations were negatively related to proximal femur and rib BMDs and total body bone mineral content, but not to LS BMD. These were stronger for bone resorption markers. Uncoupling of ongoing normal bone resorption from suppressed bone formation may therefore contribute to glucocorticoid-associated bone loss in asthma. Adrenal androgen suppression may also increase the susceptibility of postmenopausal women in particular to bone loss with OG. Although the effects of high-dose IG on BMD are associated with lower LS BMD in men, this observation should now be investigated further in prospective studies.
Notes: Clinical Trial
Controlled Clinical Trial
Author Address: The Royal Melbourne Hospital, Department of Medicine, The University of Melbourne, Victoria, Australia.
Title: Influence of Inhaled Corticosteroids and Dietary Intake on Bone Density and Metabolism in Patients with Moderate to Severe Asthma
Author: Gagnon, L.; Boulet, L. P.; Brown, J.; Desrosiers, T.; (Date: Dec, 1997)
Journal: J Am Diet Assoc; V. 97; Issue: 12; Pages: 1401-6
Abstract: OBJECTIVES: Compare the effect of high doses of inhaled corticosteroids on bone loss in subjects with moderate to severe asthma or mild asthma, and examine the influence of dietary intake on bone metabolism. DESIGN: A survey on the effects of corticotherapy and nutrition on bone density was conducted in 74 subjects currently being treated for asthma in the asthma clinic of Hopital Laval (Sainte-Foy, Quebec, Canada). Fifty-eight subjects completed the study (attrition rate = 15%). MAIN OUTCOME MEASURES: In all subjects expiratory volumes were determined and urinary analysis was conducted for hydroxyproline, calcium, phosphorus, and cortisol levels. Osteocalcin, calcium, phosphorus, cortisol, alkaline phosphatase, and gamma-glutamyltransferase levels were measured in blood samples. Bone density of the lumbar spine was determined by means of dual-energy x-ray absorptiometry. Nutrition evaluation was based on a 3-day food diary analyzed using progiciel Nutri 91. The nutritional parameters examined were calcium; phosphorus; magnesium; zinc; vitamins A, C, and D; protein; total fiber; oxalates; energy; caffeine; and alcohol in relation to bone density. SUBJECTS: Thirty-one patients with moderate to severe asthma who had been taking more than 1,000 micrograms beclomethasone per day or the equivalent for more than 2 years and 27 patients with mild asthma who were taking less than 500 micrograms beclomethasone per day or the equivalent. STATISTICAL ANALYSES PERFORMED: Four-factor analysis of variance with hierarchized interactions of four levels, Duncan’s test, Pearson correlation coefficients. RESULTS: Blood levels of osteocalcin and protein intake were lower in patients with moderate to severe asthma than in those with mild asthma (P < .05). Significant correlations (P < .02) were observed between bone density and calcium intake (r = .40), phosphorus intake (r = .35), protein intake (r = .30), and serum alkaline phosphatase level (r = -.30). Bone density was not significantly different between the two groups of patients with asthma. APPLICATIONS: A follow-up of patients with asthma who are taking inhaled corticosteroids is needed to assess bone density, osteocalcin levels, and dietary intakes of calcium. Verify if osteocalcin level decreases over time in patients with moderate to severe asthma, monitor possible modifications in bone density, and verify if the correlation between dietary calcium and bone density is maintained.
Notes: Journal Article
Author Address: Centre de recherche en pneumologie, l’Hopital Laval, Sainte-Foy, Quebec, Canada.
Notes: Journal Article
Author Address: Department of Paediatrics, School of Medicine, University of Auckland, New Zealand.
Abstract: Purified rat CD4+ T cells were activated in vitro, by the polyclonal mitogen Concanavalin A (Con A) or by mixed lymphocyte reaction (MLR), in the presence or absence of the glucocorticoid dexamethasone (DEX). They were then expanded in IL-2 and subsequently restimulated, this time in the absence of the hormone. The results indicate that the exposure of the cells to DEX in the primary stimulation changed the cytokine synthesis induced by the secondary stimulation. IL-4 production was increased by the pretreatment whereas synthesis of IFN-gamma was diminished. Addition of DEX in the second activation suppressed all cytokine production. In brief, the transient presence of glucocorticoids in the culture induces a change in the pattern of cytokine production but the continuous presence causes inhibition of cytokine synthesis. Further studies in which IL-4 was used together with DEX showed that the cytokine potentiated the effect of the hormone. The data here presented suggest that glucocorticoids and the neuroendocrine system may be expected to have long-term immunological effects as well as short-lived immunosuppressive ones. High concentration of glucocorticoids suppress cytokine production but when steroids return to basal levels the immune response is directed in a way that favors Th2-type reactions. Possible implications regarding the immune response to pathogens and autoantigens are discussed.
Notes: Journal Article
Author Address: Medical Research Council, Sir William Dunn School of Pathology, University of Oxford.