Peripheral tolerance to allergens is mediated in large part by the naturally occurring lung CD4+CD25+ T cells, but their effects on allergen-induced airway responsiveness have not been well defined. Intratracheal, but not i.v., administration of naive lung CD4+CD25+ T cells before allergen challenge of sensitized mice, similar to the administration of the combination of rIL-10 and rTGF-β, resulted in reduced airway hyperresponsiveness (AHR) and inflammation, lower levels of Th2 cytokines, higher levels of IL-10 and TGF-β, and less severe lung histopathology. Significantly, CD4+CD25+ T cells isolated from IL-10−/− mice had no effect on AHR and inflammation, but when incubated with rIL-10 before transfer, suppressed AHR, and inflammation, and was associated with elevated levels of bronchoalveolar lavage TGF-β levels. By analogy, anti-TGF-β treatment reduced regulatory T cell activity. These data identify naturally occurring lung CD4+CD25+ T cells as capable of regulating lung allergic responses in an IL-10- and TGF-β-dependent manner.

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Rationale: Leukotriene B 4 (LTB 4 ) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B 4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB 4 -BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB 4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1 Ϫ/Ϫ ) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1 Ϫ/Ϫ mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-13 levels and numbers of IL-13 ϩ /CD4 ϩ and IL-13 ϩ /CD8 ϩ T cells were also reduced in BLT1 Ϫ/Ϫ mice. Reconstitution of sensitized and challenged BLT1 Ϫ/Ϫ mice with allergen-sensitized BLT1 ϩ/ϩ T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. Conclusion: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.Keywords: airway responsiveness; cytokines; lipid mediators; lung inflammation; T cells Airway hyperresponsiveness (AHR) is the result of complex pathophysiologic changes in the airways and is a predominant feature of allergic asthma. Allergen-specific memory T cells and antibody are thought to play a central role in the development of this response (1-3). Studies in both humans and rodents have indicated that in addition to CD4 ϩ T cells, CD8 ϩ T cells may play an important role in the development of allergic airway responses (4-9).Leukotriene B 4 (LTB 4 ) is a potent lipid inflammatory mediator derived from membrane phospholipids by sequential actions of cytosolic phospholipase A 2 , 5-lipoxygenase, and leukotriene (Received in original form February 9, 2005; accepted A 4 hydrolase (10, 11). LTB 4 is a chemoattractant for leukocytes, including neutrophils, macrophages, monocytes, and eosinophils (12-15). LTB 4 activates leukocytes through a G protein-coupled cell surface receptor, leukotriene B 4 receptor 1 (BLT1) (16,17). BLT1 has been shown to be expressed on effector T cells and the LTB 4 -BLT1 pathway may be important in effector T-cell movement to sites of acute inflammation (18,19).The present study investigated the role of BLT1 in the development of allerg...

Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8−/−) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (TEFF). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated TEFF recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1−/−, CD8+ T cells into sensitized and challenged CD8−/− mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8−/− mice, in vitro-generated BLT1+/+, but not BLT1−/−, TEFF accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ TEFF recruitment into the lung and development of AHR and airway inflammation.

nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

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Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B4 (LTB4), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161–167). However, the role for the LTB4-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1−/−) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1−/− BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1−/− BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1−/− BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1+/+ BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.