Publications

Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high neutrophils isolated from the CNS of mice with experimental autoimmune encephalomyelitis. Proportions of neutrophils were markedly increased in the CNS of IFN-gamma-deficient mice. Strikingly, CNS-derived neutrophils, whether or not they derived from IFN-gamma-deficient mice, were potent suppressors of T cell responses to myelin or adjuvant Ags. Neutrophil suppressor activity was absolutely dependent on IFN-gamma production by target T cells, and suppression was abrogated by blocking NO synthase. These data identify an immunoregulatory capacity for neutrophils, and indicate that interplay between IFN-gamma, NO, and activated Gr-1high neutrophils within the target organ determines the outcome of inflammatory and potentially autoimmune T cell responses.

BACKGROUND

Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period.

METHODS

In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life.

RESULTS

The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P<0.001), the percentage of eosinophils in sputum (P=0.007), exhaled nitric oxide levels (P=0.006), scores for asthma control (P<0.001), and the number of symptom-free days (P=0.03), but not in post-bronchodilator FEV1 (P=0.29) or in the quality of life (P=0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.

CONCLUSIONS

It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended.

The diurnal rhythm of cortisol secretion in chronic disease can reflect the interactions between exogenous and endogenous factors. Exogenous glucocorticoid use may impact salivary cortisol measurements, but this has not been well-studied in ambulatory settings. In this report salivary cortisol levels were used to evaluate aspects of the diurnal rhythm of cortisol secretion within an ambulatory population of patients with asthma and allergic rhinitis. 183 persons with asthma with or without concomitant rhinitis and 34 persons with rhinitis alone were asked to collect at home, two saliva samples, 30 min after awakening and 12h later. The salivary cortisol levels were quantified by enzyme immunoassay. The recent use of glucocorticoids in the study group was determined by interview and direct examination of medications. We report that the median salivary cortisol levels 30 min post-awakening significantly differed by exogenous steroid status: no glucocorticoid use (n = 91), 10.1 nmol/l; nasal gluco-corticoid use alone (n = 25), 11.4 nmol/l; inhaled glucocorticoids (with or without concomitant nasal glucocorticoids; n = 76), 9.0 nmol/l; systemic glucocorticoids (n = 17), 4.0 nmol/l; (P = 0.02). 12-h post-awakening salivary cortisol values among the groups were similar (P = 0.85). The median 30-min post-awakening cortisol differed significantly by type and amount of inhaled steroid used: non-fluticasone users (n = 21), 11.5 nmol/l; lower dose fluticasone (<800 microg per day, n = 35); 9.2 nmol/l; and higher dose fluticasone (> or =800 microg, n=20), 5 nmol/l; (P=0.01). We conclude that in an ambulatory setting, exogenous glucocorticoid use can decrease the 30 min post-awakening but not the 12-h post-awakening salivary cortisol levels, an effect that should be taken into account in assessing the effects of other potential determinants on cortisol secretion.