[Show abstract][Hide abstract] ABSTRACT: CD45, a type I transmembrane protein tyrosine phosphatase expressed on nucleated hemopoietic cells, is prominently involved in T cell activation. Ligation of CD45RB isoforms has been associated with transplant tolerance. A recent genotyping analysis of asthma indicates a correlation with CD45 splicing. In this study, we administered an anti-CD45RB mAb (aCD45) in a murine model of allergic asthma and found that CD45RB ligation decreases allergic responses. aCD45 decreases allergen-induced pulmonary eosinophilia, bronchoalveolar lavage IL-13, IgE, and airway responses. Also, aCD45 increases the expression of CTLA4, a negative regulator of T cell activation. Furthermore, CD45RB signals no longer decrease allergic inflammation when CTLA4 is inhibited. These data support a role for CTLA4 in CD45RB-mediated inhibition of allergic inflammation. T cells and splenocytes stimulated with aCD45 exhibited increased CTLA4 levels, and analysis of CTLA4 promoter gene constructs identified a CD45RB-inducible regulatory region localized from -335 to -62 bp relative to the transcription start site. Together, these findings suggest that CD45RB signals mediate a novel role in the modulation of allergic inflammation, orchestrated by T cells through induction of CTLA4 transcription.
The Journal of Immunology 10/2007; 179(6):4212-8. DOI:10.4049/jimmunol.179.6.4212 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptors (TLRs) recognize highly conserved microbial molecular patterns, such as found in endotoxin. This study tested whether TLR4 and TLR2 stimulation in vivo would modulate subsequent adaptive (allergic) immune responses. We analyzed the effects of pulmonary administration of a TLR4 agonist, lipid A (LpA), and two TLR2 agonists, peptidoglycan (Ppg) and PamCys, in a murine model of allergic inflammation. The TLR agonists were administered during allergen sensitization or challenge. Both TLR agonists decreased the allergen-induced pulmonary recruitment of eosinophils when administered at sensitization or challenge. When given before sensitization, the TLR4 and TLR2 agonists decreased additional allergen-induced parameters of inflammation (pulmonary eosinophilia, bronchoalveolar lavage IL-13, total serum IgE, and airway hyperresponsiveness). Interestingly, TLR4 and TLR2 agonists decreased the number of CD4+ cells in the lung. Also, at the site of local allergen stimulation, the draining thoracic lymph nodes, allergen-induced lymphocyte proliferation, and IL-13 secretion were decreased by administration of LpA and Ppg. These data provide a distinct example of the modulation of adaptive (allergic) responses by non-antigen-dependent stimuli. Our findings also demonstrate that both TLR4 and TLR2 agonists decrease allergic responses, supporting the concept that exposure to bacterial components under defined conditions may protect against allergic disease.
American Journal of Respiratory Cell and Molecular Biology 04/2005; 32(3):218-24. DOI:10.1165/rcmb.2003-0435OC · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The collectin surfactant protein D (SP-D) confers protection against pulmonary infection and inflammation. Recent data suggest a role for SP-D in the modulation of allergic inflammation.
The aim of this study is to characterize the immune responses of SP-D-deficient (SP-D(-/-)) mice in a kinetic model of allergic inflammation. We determined whether allergic parameters were enhanced in SP-D(-/-) mice in vivo. Further, we examined whether functional immune responses in vitro such as lymphocyte proliferation (LP) and cytokine production were modulated in the absence of SP-D.
In vivo, wild-type (WT) and SP-D(-/-) mice were sensitized and challenged with the allergen ovalbumin (OVA) and assessed for allergic parameters (bronchoalveolar lavage (BAL) eosinophils, IL-13 production, pulmonary IFN-gamma, IL-10 expression) at early time points (1 and 3 days of challenge) in comparison with late time points (7 days of challenge). In vitro, spleen cells from WT and SP-D(-/-) mice were stimulated with the mitogen concanavalin A (ConA) and lipid A (LpA) and analysed for LP, IL-13 and IFN-gamma production. Toll-like receptor 4 (TLR4), ligand for LpA, was assessed by mRNA expression and immunohistochemistry in vivo.
Following allergen exposure in vivo, SP-D(-/-) mice expressed higher BAL eosinophils and IL-13 concentrations and lower IFN-gamma expression at early time points compared with WT mice. IL-10 expression was increased at early time points in SP-D(-/-) compared with WT mice. Allergen-induced TLR4 expression was increased in WT, but not in SP-D(-/-) mice. After stimulation with LpA and ConA in vitro LP was increased and IFN-gamma concentration was decreased in SP-D(-/-) mice.
SP-D may be critical for the modulation of early stages of allergic inflammation in vivo.
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptor 2 (TLR2) and TLR4 signaling may induce differential secretion of T helper 1 (Th1) and Th2 cytokines, potentially influencing the development of autoimmune or atopic diseases. To date, the influence of the type of stimulus, timing, and dose of TLR2 and TLR4 ligands on cytokine secretion has not been well established. We tested whether the innate stimuli peptidoglycan (Ppg, TLR2 agonist) and lipid A (LpA, TLR4 agonist) differentially affect the secretion of interleukin-13 (IL-13) (Th2) and interferon-gamma (IFN-gamma) (Th1). Further, we examined the influence of the maturity of the immune system, species, dose, and timing of stimuli in human cord and adult peripheral blood mononuclear cells (PBMC) and murine cells in vitro and in vivo. Stimulation with Ppg induced the secretion of both IL-13 and IFN-gamma, influenced by time and dose in neonates, adults, and mice. In contrast, stimulation with LpA induced primarily time-independent and dose-independent production of IFN-gamma. Pulmonary administration of Ppg in vivo in mice resulted in secretion of IL-13, whereas administration of LpA resulted in secretion of IFN-gamma in bronchoalveolar lavage (BAL). Therefore, TLR2 and TLR4 stimuli differentially influence IL-13 and IFN-gamma secretion in neonates, adults, and mice, supporting a critical role for innate stimuli in the modulation of cytokine responses.
Journal of Interferon & Cytokine Research 10/2004; 24(9):543-52. DOI:10.1089/jir.2004.24.543 · 2.00 Impact Factor