-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. OBJECTIVES: We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. METHODS: Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. RESULTS: OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. CONCLUSIONS: In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection.
The Journal of allergy and clinical immunology 10/2012; · 9.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Naturally occurring Foxp3(+)CD4(+)CD25(+) T regulatory cell (nTreg)-mediated suppression of lung allergic responses is abrogated following ligation of glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein. In vitro stimulation of nTregs with GITR ligand increased phosphorylation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinase (ERK) or p38 MAPK. SP600125, a known JNK inhibitor, prevented GITR-mediated phosphorylation of JNK. Activation of JNK was associated with increases in the upstream mitogen-activated protein kinase kinase 7 (MKK7) and the downstream transcription factor NF-κβ. Phosphorylated c-Jun (p-c-Jun), indicative of the activation of JNK, was detected in the immunoprecipitates of nTregs from wild-type but not JNK- or GITR-deficient mice. Treatment with an inhibitor of JNK phosphorylation resulted in complete reversal of all GITR-induced changes in nTreg phenotype and function, with full restoration of suppression of in vivo lung allergic responses and in vitro proliferation of activated CD4(+)CD25(-) T cells. Thus, regulation of JNK phosphorylation plays a central role in T regulatory cell function with therapeutic implications for the treatment of asthma and autoimmune diseases.
Journal of Biological Chemistry 03/2012; 287(21):17100-8. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Naturally occurring CD4(+)CD25(+)Foxp3(+) T regulatory cells (nTregs) regulate lung allergic responses through production of IL-10 and TGF-β. nTregs from CD8(-/-) mice failed to suppress lung allergic responses and were characterized by reduced levels of Foxp3, IL-10, and TGF-β, and high levels of IL-6. Administration of anti-IL-6 or anti-IL-6R to wild-type recipients prior to transfer of CD8(-/-) nTregs restored suppression. nTregs from IL-6(-/-) mice were suppressive, but lost this capability if incubated with IL-6 prior to transfer. The importance of CD8 in regulating the production of IL-6 in nTregs was demonstrated by the loss of suppression and increases in IL-6 following transfer of nTregs from wild-type donors depleted of CD8(+) cells. Transfer of nTregs from CD8(-/-) donors reconstituted with CD8(+) T cells was suppressive, and accordingly, IL-6 levels were reduced. These data identify the critical role of CD8-T regulatory cell interactions in regulating the suppressive phenotype of nTregs through control of IL-6 production.
The Journal of Immunology 01/2011; 186(1):113-20. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although implicated in the disease, the specific contributions of FcepsilonRI and IL-13 to the pathogenesis of peanut-induced intestinal allergy are not well defined.
We sought to determine the contributions of FcepsilonRI, IL-13, and mast cells to the development of intestinal mucosal responses in a murine model of peanut-induced intestinal allergy.
Sensitized wild-type (WT), FcepsilonRI-deficient (FcepsilonRI(-/-)), and mast cell-deficient (Kit(W-sh/W-sh)) mice received peanut orally every day for 1 week. Bone marrow-derived mast cells (BMMCs) from WT, FcepsilonRI(-/-), IL-4(-/-), IL-13(-/-), and IL-4/IL-13(-/-) mice were differentiated and transferred into WT, FcepsilonRI(-/-), and Kit(W-sh/W-sh) recipients. BMMCs from WT and UBI-GFP/BL6 mice were differentiated and transferred into WT and Kit(W-sh/W-sh) mice. Blockade of IL-13 was achieved by using IL-13 receptor alpha2 (IL-13Ralpha2)-IgG fusion protein.
FcepsilonRI(-/-) mice showed decreased intestinal inflammation (mast cell and eosinophil numbers) and goblet cell metaplasia and reduced levels of IL4, IL6, IL13, and IL17A mRNA expression in the jejunum. Transfer of WT BMMCs to FcepsilonRI(-/-) recipients restored their ability to develop intestinal allergic responses unlike transfer of FcepsilonRI(-/-), IL-13(-/-), or IL-4/IL-13(-/-) BMMCs. FcepsilonRI(-/-) mice exhibited lower IL-13 levels and treatment of WT mice with IL-13 receptor alpha2 prevented peanut-induced intestinal allergy and inflammation.
These data indicate that the development of peanut-induced intestinal allergy is mediated through a mast cell-dependent IgE-FcepsilonRI-IL-13 pathway. Targeting IL-13 might be a potential treatment for IgE-mediated peanut-induced allergic responses in the intestine.
The Journal of allergy and clinical immunology 08/2010; 126(2):306-16, 316.e1-12. · 9.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA-alpha-galactosylceramide (OVA/alphaGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/alphaGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alphaGalCer BMDCs into IFN-gamma-deficient (IFN-gamma(-/-)) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-gamma treatment following OVA-BMDC transfer. Further, Jalpha18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/alphaGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in Jalpha18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alphaGalCer BMDC transfer. iNKT cells from these IFN-gamma(-/-) mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-gamma as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.
The Journal of Immunology 07/2010; 185(1):253-62. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Respiratory syncytial virus (RSV) bronchiolitis in infants may be followed by the development of asthma-like symptoms. Age at first infection dictates consequences upon reinfection. Reinfection of mice initially exposed as neonates to RSV enhanced development of airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus hyperproduction. RSV lower respiratory tract disease is associated with activation of the leukotriene pathway.
To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice.
BALB/c mice were infected with RSV at 1 week (neonate) or 6 to 8 weeks (adult) of age and reinfected 5 weeks later. MK was administered 1 day before the initial infection and through Day 6 after infection. Seven days after primary or secondary infection, airway function was assessed by lung resistance to increasing doses of inhaled methacholine; lung inflammation, goblet cell metaplasia, and cytokine levels in bronchoalveolar lavage fluid were monitored.
RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-gamma production in primary infected adult and neonatal mice. MK, administered during initial infection of neonates but not during secondary infection, prevented subsequent enhancement of AHR, airway eosinophilia, and mucus hyperproduction upon reinfection.
MK attenuated the initial responses to primary RSV infection in both age groups and altered the consequences of RSV reinfection in mice initially infected as neonates. These data support an important role for cysLT in RSV-induced AHR and inflammation.
American Journal of Respiratory and Critical Care Medicine 05/2010; 182(4):455-63. · 11.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-gamma (IFN-gamma) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.
Proceedings of the National Academy of Sciences 01/2010; 107(1):320-5. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells isolated from lungs of naive mice regulate lung allergic airway hyperresponsiveness, inflammation, levels of Th2 cytokines, and mucus production. OVA-specific (alphabetaTCR(+)) CD4(+)CD25(+) T cells suppressed ragweed-induced airway hyperresponsiveness and inflammation as did anti-TCR-treated OVA-specific CD4(+)CD25(+) T cells, suggesting that Ag-specificity was not required for expression of regulatory activities. Suppression was associated with increased levels of IL-10 and TGF-beta; decreased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid; and reduced recruitment and activation of CD8(+) T cells in the airways. Following intratracheal administration, OVA-specific CD4(+)CD25(+) T cells were identified in both the airway lumens and lung parenchyma, and in some instances in close proximity to host CD8(+) T cells. These results demonstrate that the regulatory activities of naturally occurring Foxp3(+)CD4(+)CD25(+) T cells on lung allergic responses are Ag-nonspecific and thus, independent of Ag-specific recognition.
The Journal of Immunology 09/2009; 183(3):1821-7. · 5.79 Impact Factor
-
Katsuyuki Takeda,
Steven W Dow,
Nobuaki Miyahara,
Taku Kodama,
Toshiyuki Koya,
Christian Taube,
Anthony Joetham,
Jung-Won Park, Azzeddine Dakhama,
Ross M Kedl,
Erwin W Gelfand
[show abstract]
[hide abstract]
ABSTRACT: Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice.
The Journal of Immunology 08/2009; 183(1):181-90. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ligation of the leukotriene B(4) (LTB(4)) receptor 1 on effector memory CD8(+) T cells by LTB(4) is important for the recruitment of CD8(+) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types.
The roles of ERKs in effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR were determined.
Effector CD8(+) T cells were generated from OVA(257-264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR and allergic inflammation were examined.
Pretreatment of effector CD8(+) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB(4)-induced Ca(2+) mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8(+) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8(+) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment.
ERK1/2-dependent pathways are essential for the effector functions of CD8(+) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8(+) T cell-mediated AHR.
The Journal of allergy and clinical immunology 02/2009; 123(1):249-57. · 9.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dendritic cells (DCs) are considered to be the most efficient antigen-presenting cells. Intratracheal administration of allergen-pulsed bone marrow-derived dendritic cells (BMDCs) before allergen challenge induces airway hyperresponsiveness (AHR) and inflammation. Ovalbumin (OVA)-pulsed BMDCs from wild-type (WT) mice were transferred into naive WT, CD4(-/-), CD8(-/-), or IL-13(-/-) mice. Two days (short protocol) or 10 days (long protocol) after BMDC transfer, mice were challenged with 1% OVA for 3 days and assayed 2 days later. Transfer of OVA-primed BMDCs into BALB/c or C57BL/6 mice elicited AHR in both protocols. Airway eosinophilia, Th2 cytokines, or goblet cell metaplasia were increased in the long but not short protocol. Lung T cells from both protocols produced Th2 cytokines in response to OVA in vitro. Carboxyfluorescein diacetate succinimidylester-labeled BMDCs were observed in bronchoalveolar lavage (BAL) fluid and lung parenchyma at early time points, and were detected in draining lymph nodes 48 hours after transfer. CD8(-/-) mice developed AHR comparable to WT mice in the short protocol, but decreased levels of AHR, airway eosinophilia, Th2 cytokines in BAL fluid, and goblet cell metaplasia compared with WT mice in the long protocol. CD4(-/-) or IL-13(-/-) mice did not develop AHR or airway inflammation in either protocol. These data suggest that allergen-pulsed BMDCs initiate development of AHR that is dependent initially on CD4(+) T cells, and at later time periods on CD8+ T cells and IL-13. Thus, the timing of allergen challenge after transfer of allergen-pulsed BMDC affects the development of AHR and airway inflammation.
American Journal of Respiratory Cell and Molecular Biology 02/2009; 41(3):271-80. · 5.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Respiratory syncytial virus (RSV)-specific IgE is a component of the host response to RSV infection, but its role in the subsequent enhancement of altered airway responsiveness is unknown.
To define the role of RSV-specific IgE in the enhancement of airway responsiveness on reinfection of newborn mice.
Mice were infected as newborns with RSV and were reinfected 5 weeks later. The role of IgE was determined by documenting RSV-specific IgE response after neonatal infection, and by assessing airway responsiveness on reinfection.
After neonatal infection, wild-type (WT) mice developed an RSV-specific IgE response. On reinfection, these mice developed enhanced airway hyperresponsiveness (AHR), airway eosinophilia, and mucus hyperproduction, and their T-cell cytokine response was skewed toward a T(H)2 phenotype. None of these altered responses developed on reinfection of IL-4(-/-)/IL-13(-/-) mice, and no RSV-specific IgE could be detected after neonatal infection of these mice. Fc epsilon RI(-/-) mice did not develop the enhanced AHR on reinfection, and airway eosinophilia and mucus production were significantly attenuated. These responses could be restored in deficient mice reconstituted with WT mast cells. In RSV-infected newborn WT mice, administration of anti-IgE prevented the enhancement of AHR and attenuated eosinophilia and mucus hyperproduction on reinfection, an effect that was associated with diminished T(H)2 cytokine production and increased IFN-gamma production.
Respiratory syncytial virus-specific IgE enhances the development of T(H)2-biased airway responsiveness on reinfection of mice initially infected as newborns.
The Journal of allergy and clinical immunology 01/2009; 123(1):138-145.e5. · 9.17 Impact Factor
-
Nobuaki Miyahara,
Hiroshi Ohnishi,
Satoko Miyahara,
Katsuyuki Takeda,
Shigeki Matsubara,
Hiroyuki Matsuda,
Masakazu Okamoto,
Joan E Loader,
Anthony Joetham,
Mitsune Tanimoto, Azzeddine Dakhama,
Erwin W Gelfand
[show abstract]
[hide abstract]
ABSTRACT: Previous studies have shown that leukotriene B4 (LTB4), a proinflammatory lipid mediator, is linked to the development of airway hyperresponsiveness through the accumulation of IL-13-producing CD8+ T cells, which express a high affinity receptor for LTB4, BLT1 (Miyahara et al., Am J Respir Crit Care Med 2005;172:161-167; J Immunol 2005;174:4979-4984). By using leukotriene A4 hydrolase-deficient (LTA4H-/-) mice, which fail to synthesize LTB4, we determined the role of this lipid mediator in allergen-induced airway responses. Two approaches were used. In the first, LTA4H-/- mice and wild-type (LTA4H+/+) mice were systemically sensitized and challenged via the airways to ovalbumin. In the second, mice were passively sensitized with anti-ovalbumin IgE and exposed to ovalbumin via the airways. Mast cells were generated from bone marrow of LTA4H+/+ mice or LTA4H-/- mice. After active sensitization and challenge, LTA4H-/- mice showed significantly lower airway hyperresponsiveness compared with LTA4H+/+ mice, and eosinophil numbers and IL-13 levels in the bronchoalveoloar lavage of LTA4H-/- mice were also significantly lower. LTA4H-/- mice also showed decreased airway reactivity after passive sensitization and challenge. After LTA4H+/+ mast cell transfer, LTA4H-/- mice showed increased airway reactivity after passive sensitization and challenge, but not after systemic sensitization and challenge. These data confirm the important role for LTB4 in the development of altered airway responses and suggest that LTB4 secretion from mast cells is critical to eliciting increased airway reactivity after passive sensitization with allergen-specific IgE.
American Journal of Respiratory Cell and Molecular Biology 12/2008; 40(6):672-82. · 5.13 Impact Factor
-
Shigeki Matsubara,
Katsuyuki Takeda,
Niyun Jin,
Masakazu Okamoto,
Hiroyuki Matsuda,
Yoshiki Shiraishi,
Jung Won Park,
Glen McConville,
Anthony Joetham,
Rebecca L O'Brien, Azzeddine Dakhama,
Willi K Born,
Erwin W Gelfand
[show abstract]
[hide abstract]
ABSTRACT: gammadelta T cells regulate airway reactivity, but their role in ozone (O3)-induced airway hyperresponsiveness (AHR) is not known. Our objective was to determine the role of gammadelta T cells in O3-induced AHR. Different strains of mice, including those that were genetically manipulated or antibody-depleted to render them deficient in total gammadelta T cells or specific subsets of gammadelta T cells, were exposed to 2.0 ppm of O3 for 3 hours. Airway reactivity to inhaled methacholine, airway inflammation, and epithelial cell damage were monitored. Exposure of C57BL/6 mice to O3 resulted in a transient increase in airway reactivity, neutrophilia, and increased numbers of epithelial cells in the lavage fluid. TCR-delta(-/-) mice did not develop AHR, although they exhibited an increase in neutrophils and epithelial cells in the lavage fluid. Similarly, depletion of gammadelta T cells in wild-type mice suppressed O3-induced AHR without influencing airway inflammation or epithelial damage. Depletion of Vgamma1+, but not of Vgamma4+ T cells, reduced O3-induced AHR, and transfer of total gammadelta T cells or Vgamma1+ T cells to TCR-delta(-/-) mice restored AHR. After transfer of Vgamma1+ cells to TCR-delta(-/-) mice, restoration of AHR after O3 exposure was blocked by anti-TNF-alpha. However, AHR could be restored in TCR-delta(-/-)mice by transfer of gammadelta T cells from TNF-alpha-deficient mice, indicating that another cell type was the source of TNF-alpha. These results demonstrate that TNF-alpha and activation of Vgamma1+ gammadelta T cells are required for the development of AHR after O3 exposure.
American Journal of Respiratory Cell and Molecular Biology 11/2008; 40(4):454-63. · 5.13 Impact Factor
-
Nobuaki Miyahara,
Hiroshi Ohnishi,
Hiroyuki Matsuda,
Satoko Miyahara,
Katsuyuki Takeda,
Toshiyuki Koya,
Shigeki Matsubara,
Masakazu Okamoto, Azzeddine Dakhama,
Bodduluri Haribabu,
Erwin W Gelfand
[show abstract]
[hide abstract]
ABSTRACT: Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B(4) (LTB(4)), interacting with its high-affinity receptor, LTB(4) 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 LTB(4)-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.
The Journal of Immunology 08/2008; 181(2):1170-8. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activation of CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T cells (nTregs) resulting in suppression of lung allergic responses requires interaction of MHC class I on nTregs and CD8. In the absence of CD8 (CD8(-/-) recipients), transferred nTregs restored airway hyperresponsiveness, eosinophilic inflammation, and IL-13 levels following allergen exposure. Enhancement of lung allergic responses was accompanied by reduced expression of Foxp3 and increased expression of IL-13 in the transferred nTregs. In CD8(-/-) recipients pretreated with glucocorticoid-induced TNFR-related protein-ligand Ab, the transferred nTregs maintained high levels of Foxp3 and did not result in altered lung responses. Thus, the regulatory function of nTregs can be subverted by reducing the expression of Foxp3 and following signaling through glucocorticoid-induced TNFR-related protein are converted nTregs into IL-13-producing CD4(+) T cells mediating lung allergic responses.
The Journal of Immunology 07/2008; 180(11):7117-24. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist. These results demonstrate that sex differences in 10-day OVA-induced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.
American Journal of Respiratory Cell and Molecular Biology 06/2008; 38(5):501-8. · 5.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Adoptive transfer of in vivo-primed CD8(+) T cells or in vitro-generated effector memory CD8(+) T (T(EFF)) cells restores airway hyperresponsiveness (AHR) and airway inflammation in CD8-deficient (CD8(-/-)) mice. Examining transcription levels, there was a strong induction of Notch1 in T(EFF) cells compared with central memory CD8(+) T cells. Treatment of T(EFF) cells with a gamma-secretase inhibitor (GSI) strongly inhibited Notch signaling in these cells, and after adoptive transfer, GSI-treated T(EFF) cells failed to restore AHR and airway inflammation in sensitized and challenged recipient CD8(-/-) mice, or to enhance these responses in recipient wild-type (WT) mice. These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T(EFF) cells. Treatment of sensitized and challenged WT mice with Delta1-Fc resulted in decreased AHR and airway inflammation accompanied by higher levels of interferon gamma in bronchoalveolar lavage fluid. These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1. These data are the first to show a functional role for Notch in the challenge phase of CD8(+) T cell-mediated development of AHR and airway inflammation, and identify Delta1 as an important regulator of allergic airway inflammation.
Journal of Experimental Medicine 06/2008; 205(5):1087-97. · 13.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Leukotriene B4 (LTB4) is a potent inflammatory lipid mediator that binds to LTB4 receptor 1 (BLT1). Ligation of BLT1 by LTB4 plays an important role in the recruitment of effector memory CD8+ T cells into the airways of sensitized and challenged mice.
The effects of the corticosteroid dexamethasone (DEX) on BLT1-expressing effector memory CD8+ T cells and effector memory CD8+ T cell-mediated airway hyperresponsiveness (AHR) and allergic inflammation were determined.
Effector memory CD8+ T cells were generated from ovalbumin(257-264)-primed mononuclear cells from OT-1 mice in the presence of IL-2. In some cultures DEX was added. The effects of DEX on BLT1 expression, LTB4-induced Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, chemotaxis, and effector memory CD8+ T cell-mediated AHR were examined.
DEX-treated effector memory CD8+ T cells showed significant increases in surface expression of BLT1, LTB4-induced intracellular Ca2+ influx, phosphorylation of extracellular signal-regulated kinase 1/2, and chemotaxis. Upregulation of BLT1 by DEX was accompanied by increased IL-2 receptor expression. Adoptive transfer of DEX-treated effector memory CD8+ T cells into ovalbumin-sensitized and ovalbumin-challenged CD8-/- mice resulted in significant increases in AHR, allergic inflammation, goblet cell metaplasia, and numbers of both CD8+ and CD4+ T cells in the bronchoalveolar lavage fluid and lungs.
Corticosteroids upregulate BLT1 on effector memory CD8+ T cells and related signaling pathways and potentiate allergic airway inflammation and AHR induced by these cells.
The Journal of allergy and clinical immunology 05/2008; 121(4):864-71.e4. · 9.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The relative contributions of the allergen-specific early-phase nasal response and nonspecific nasal response and mast cells to the pathophysiology of allergic rhinitis are not well defined.
To determine the contributions of specific reactivity, nonspecific reactivity, and mast cells to the development of early-phase and late-phase responses using a mouse model of allergic rhinitis.
Sensitized wild-type and FcvarepsilonRI-deficient (FcvarepsilonRI-/-) mice were exposed to allergen for 3, 5, or 12 days. As indicators of nasal reactivity, respiratory frequency and nasal resistance were monitored.
Sensitized mice exposed to 3 days of nasal allergen challenge showed a nonspecific early-phase response. As the number of allergen exposures increased, there was progressive diminution in nonspecific responses with increased allergen-specific early-phase responses and a late-phase response. Sensitized FcvarepsilonRI-/- mice did not develop nonspecific nasal responses or late-phase responses, but transfer of in vitro-differentiated wild-type mast cells into FcvarepsilonRI-/- mice restored nonspecific early-phase nasal responses but not the late-phase response.
These data identify the nonspecific nasal response as a major contributor to the early-phase response, especially during initial allergen exposure, and is dependent on mast cells. Increasing allergen exposure results in increasing allergen-specific responses, converting the nonspecific early-phase response to a late-phase response that is allergen-specific and mast cell-independent.
The Journal of allergy and clinical immunology 04/2008; 121(3):718-24. · 9.17 Impact Factor
