Local and systemic immunological parameters associated with remission of asthma symptoms in children.

The immunological and clinical parameters that are associated with asthma remission are poorly understood. The cytokine and local mediator changes associated with the resolution of asthma symptoms were examined in three groups of subjects 12-18 years of age (n = 15 in each group): (a) continuing asthma group (CA) who had persistent symptoms since early childhood, (b) an age, sex and atopic status-matched group who had persistent symptoms in early childhood but in whom these had resolved (RA), and (c) a non-atopic, non-asthmatic control group. Clinical parameters, sputum cell counts, peripheral blood mononuclear cell (PBMC) cytokine production and activation marker expression were determined. All of the CA had methacholine airway hyperresponsiveness compared with only half of the RA subjects. The CA showed elevated numbers of eosinophils and increased ECP and IL-5 in sputum, which were not observed in the RA. PBMC cytokine studies revealed increased production of the type 1 cytokines IL-12, IFN-γ and TNF-α in the CA group compared with the RA group, under a range of activation conditions, however, the production of IL-4 and IL-5 were unchanged. These findings suggest that decreased type 1 cytokine expression as well as decreased eosinophilic inflammation is associated with the resolution of asthma symptoms.

Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation.

BACKGROUND: Histologic and immunohistologic features of nasal polyps (NP) are similar to those observed in asthma, thus suggesting a similar immunopathology. OBJECTIVE: The primary objective of this study was to further understand the anti-inflammatory and immunoregulatory effects of locally delivered corticosteroids. To this end, the effect of intranasal budesonide on the expression of specific cytokines, lymphocyte subsets, and epithelial remodeling in this model of airway tissue inflammation were studied. METHODS: We used immunohistochemical techniques to examine nasal mucosae (NM) from healthy individuals and nasal polyp (NP) tissues from patients with nasal polyposis obtained before and after intranasal budesonide treatment. RESULTS: First, the density of CD8(+) cells was markedly increased in NP tissues after intranasal budesonide treatment from 16.1 +/- 8.4 (M +/- SEM) per mm(2) to 39.9 +/- 24.1. Second, the density of cells immunoreactive for IL-4, IL-5, IFN-gamma, IL-12, and TGF-beta in NP was significantly greater than in control NM tissues. The density of IL-4(+) and IL-5(+) cells in NP tissues significantly decreased after budesonide treatment from 40 +/- 12 to 17.8 +/- 8 and from 19.3 +/- 11 to 10.4 +/- 7, respectively. In contrast, the density of IFN-gamma(+) and IL-12(+) cells remained unchanged. In addition, we found that the density of TGF-beta(+) cells significantly increased after intranasal budesonide from 18 +/- 5 to 41 +/- 9. Third, damage to the entire length of the NP epithelium was quantified using a grading system. The epithelium of untreated NP was substantially damaged; remarkable epithelial restitution with no apparent changes in stromal collagen deposition was observed after intranasal budesonide treatment. CONCLUSIONS: These findings demonstrate that intranasal budesonide induced an increase in CD8 population and a selective regulatory effect on tissue cytokine expression. Furthermore, intranasal budesonide promoted epithelial remodeling. We hypothesize that these immunoregulatory and remodeling effects elicited by steroids might be, at least in part, mediated by the induction of TGF-beta.

Microenvironmental Control of Inflammatory Cell Differentiation.

A wide body of information now exists on hemopoietic and proinflammatory cytokine production by structural cells of the microenvironment. Included among these are epithelial cells, endothelial cells and fibroblasts which can, either constitutively or upon stimulation with other cytokines or lipopoly-saccharide, express the genes for, and produce, IL-6, IL-8, G-CSF, GM-CSF, and M-CSF, as well as yet unidentified cytokines with prominent cell differentiation-inducing activities. Inflammatory cells which accumulate at sites of allergic-type reactions include granulocytes such as basophils, eosinophils and mast cells, as well as neutrophils and cells of the monocyte-macrophage lineage. Combinations of cytokines produced by tissue structural cells have been studied with reference to their capacity to induce differentiation, activate and prolong the survival of inflammatory cells. Evidence can be adduced for the differentiation process being intimately connected to phenotype switch and activation of cells, such as eosinophils and mast cells, which themselves can feed back upon this by production of cytokines such as TGF-ß and GM-CSF; the production of T cell-derived cytokines such as IL-3, IL-5 and GM-CSF can be shown to contribute to basophil and eosinophil differentiation and activation. Work from our laboratory will be summarized with reference to the syntax and language of structural cell-derived cytokines in terms of inflammatory cell differentiation pathways, using a variety of in vitro and in vivo detection techniques. Application of these findings to the control of inflammatory reactions as well as wound repair will also be discussed.