Th2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18-24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-gamma in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-gamma treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-gamma. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.
Human Studies Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
The interaction between air particulates and genetic susceptibility has been implicated in the pathogenesis of asthma. The overall objective of this study was to determine the effects of inhalation exposure to environmentally relevant concentrated air particulates (CAPs) on the lungs of ovalbumin (ova) sensitized and challenged Brown Norway rats. Changes in gene expression were compared with lung tissue histopathology, morphometry, and biochemical and cellular parameters in bronchoalveolar lavage fluid (BALF). Ova challenge was responsible for the preponderance of gene expression changes, related largely to inflammation. CAPs exposure alone resulted in no significant gene expression changes, but CAPs and ova-exposed rodents exhibited an enhanced effect relative to ova alone with differentially expressed genes primarily related to inflammation and airway remodeling. Gene expression data was consistent with the biochemical and cellular analyses of the BALF, the pulmonary pathology, and morphometric changes when comparing the CAPs-ova group to the air-saline or CAPs-saline group. However, the gene expression data were more sensitive than the BALF cell type and number for assessing the effects of CAPs and ova versus the ova challenge alone. In addition, the gene expression results provided some additional insight into the TGF-beta-mediated molecular processes underlying these changes. The broad-based histopathology and functional genomic analyses demonstrate that exposure to CAPs exacerbates rodents with allergic inflammation induced by an allergen and suggests that asthmatics may be at increased risk for air pollution effects.
BACKGROUND: Trimellitic anhydride (TMA)-induced occupational asthma is thought to be associated with its ability to acylate proteins and to induce production of TMA-specific immunoglobulin (Ig)E. Though the respiratory tract is considered to be a major exposure route leading to airway sensitization, the potential role of dermal exposure producing asthmatic sensitization is not known. The present study examines the ability of dry TMA powder to sensitize Brown Norway rats when applied, topically, to the skin. METHODS: A patch of hair was carefully clipped with scissors on the rat's back. Dry TMA powder (0.3, 1.25, 5 and 20 mg) was administered on days 0, 7, 14 and 21, and the area occluded with surgical tape overnight after each application. Residual powder recovered from the occluded skin was analyzed by proton nuclear magnetic resonance and was still predominantly TMA. Circulating anti-TMA IgE and IgG were measured by ELISA. RESULTS: TMA elicited dose-dependent production of specific IgE and IgG. Specific antibodies were detectable 2 weeks after the first TMA exposure and peaked between 3 and 4 weeks. CONCLUSION: The data suggest that topical skin exposure to dry TMA powder can induce allergic/immunological sensitization as demonstrated by the production of specific antibodies.
The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response. Like adenosine, the broad-spectrum adenosine receptor agonist, NECA, induced dose-related bronchoconstriction in actively sensitized, OA-challenged animals. In contrast, CPA, CGS 21680 and 2-Cl-IB-MECA, agonists selective for A(1) A(2A) and A(3) receptors, respectively, induced no, or minimal, bronchoconstriction. Neither the selective A(1) receptor antagonist, DPCPX, nor the selective A(2A) receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine. MRS 1754, which has similar affinity for rat A(2B) and A(1) receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A(1) receptor-mediated bradycardia induced by NECA. 8-SPT and CGS 15943, antagonists at A(1), A(2A), and A(2B) but not A(3) receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the K(B) value at the rat A(2B) receptor, respectively. Adenosine and NECA, but not CPA, CGS 21680 or 2-Cl-IB-MECA, induced contraction of parenchymal strip preparations from actively sensitized OA-challenged animals. Responses to adenosine could not be antagonized by 8-SPT or MRS 1754 at concentrations >50 times their affinities at the rat A(2B) receptor. The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes.
BACKGROUND: A previous study showed a relation between pholcodine (PHO) consumption, prevalence of IgE-sensitization to PHO, morphine (MOR) and suxamethonium (SUX) and anaphylaxis to neuromuscular blocking agents (NMBA). The purpose of this pilot study was to explore the effect on IgE production, in IgE-sensitized and nonsensitized individuals, of exposure to cough syrup and environmental chemicals containing PHO, MOR and SUX related allergenic structures. METHODS: Serum concentrations of IgE and IgE antibodies to PHO, MOR and SUX allergens measured by ImmunoCAP (Pharmacia Diagnostics, Uppsala, Sweden) were followed after intake of cough syrup, or exposure to confectionary and other household chemicals containing various amounts of substances cross-reacting with PHO, MOR and SUX. RESULTS: Cough syrup containing PHO gave, in sensitized individuals, within 1-2 weeks, an increase of IgE of 60-105 times and of IgE antibodies to PHO, MOR and SUX in the order of 30-80 times. The tested confectionary did not have any similar stimulating effect but seemed to counteract the expected decrease of IgE. No effect was seen in nonsensitized individuals. The PHO stimulated IgE showed a nonspecific binding to ImmunoCAP with common allergens and glycine background ImmunoCAP that was up to 10-fold higher than that of monomeric myeloma-IgE at twice the concentration. CONCLUSIONS: It seems as cough syrups containing PHO have a most remarkable IgE boostering effect in persons IgE-sensitized to PHO, MOR and SUX related allergens. Household chemicals containing such allergenic epitopes seem capable of some, minor, stimulation.
Increased or altered collagen deposition in the airway wall is one of the characteristics of airway remodelling in asthma. The mechanisms underlying this increase, and its functional consequences remain to be established further. Representative in vivo animal models might be useful in this respect. In the present study, collagen deposition after prolonged allergen exposure was characterised in the airway wall of Brown Norway rats. Sensitised rats were repeatedly exposed to ovalbumin (OA) or phosphate-buffered saline during 2 and 12 weeks. The deposition of collagen type I, III, IV, V and VI was not altered in animals exposed to OA for 2 weeks. After 12 weeks of OA exposure, more collagen type I was deposited in the inner and outer airway wall and more type V and VI collagen was observed in the outer airway wall. At 12 weeks the number of vessels, identified via type IV collagen staining was not increased, but the total vessel area was. In conclusion, prolonged allergen exposure in sensitised rats is associated with enhanced deposition of type I, V and VI collagens and increased vascularity. This suggests that some aspects of airway remodelling in asthma could be driven by long-term allergen exposure.
Repeated ovalbumin (OA) or saline exposure of sensitized Brown Norway rats was examined on agonist reactivity, airway smooth muscle (ASM) content, and contractile protein expression in small bronchioles at 24 h, 7 days, and 35 days after challenge. OA increased ASM content (P