Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V(alpha)14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281(-/-) mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d(-/-) mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V(alpha)14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V(alpha)14i NKT cells may be clinically effective in limiting the development of AHR and asthma.
Interactions of the inhibitory receptor programmed death-1 (PD-1) with its ligands, programmed death ligand (PD-L)1 and PD-L2, regulate T-cell activation and tolerance. In this study, we investigated the role of PD-L1 and PD-L2 in regulating invariant natural killer T (iNKT)-cellmediated airway hyperreactivity (AHR) in a murine model of asthma. We found that the severity of AHR and airway inflammation is significantly greater in PD-L2 −/− mice compared with wild-type mice after either ovalbumin (OVA) sensitization and challenge or administration of α-galactosylceramide (α-GalCer). iNKT cells from PD-L2 −/− mice produced significantly more interleukin (IL)-4 than iNKT cells from control mice. Moreover, blockade of PD-L2 interactions of wild-type iNKT cells in vitro with monoclonal antibodies (mAbs) resulted in significantly enhanced levels of IL-4 production. In contrast, PD-L1 −/− mice showed significantly reduced AHR and enhanced production of interferon-γ (IFN-γ) by iNKT cells. iNKT-deficient Jα18 −/− mice reconstituted with iNKT cells from PD-L2 −/− mice developed high levels of AHR, whereas mice reconstituted with iNKT cells from PD-L1 −/− mice developed lower levels of AHR compared with control. As PD-L2 is not expressed on iNKT cells but rather is expressed on lung dendritic cells (DCs), in which its expression is upregulated by allergen challenge or IL-4, these findings suggest an important role of PD-L2 on lung DCs in modulating asthma pathogenesis. These studies also indicate that PD-L1 and PD-L2 have important but opposing roles in the regulation of AHR and iNKT-cell-mediated activation.
BackroundVisual analogue scales (VAS) are psychometric measuring instruments designed to document the characteristics of disease-related symptom severity in individual patients and use this to achieve a rapid (statistically measurable and reproducible) classification of symptom severity and disease control. VAS can also be used in routine patient history taking and to monitor the course of a chronic disease such as allergic rhinitis (AR). More specifically, the VAS has been used to assess effectiveness of AR therapy in real life, both in intermittent and persistent disease.MethodsThis position paper takes a detailed look at the historical development of VAS and its method-specific principles. Particular focus is put on aspects of practical application in daily routine and on a critical discussion of the advantages and disadvantages of the individual methods.ResultsVAS are well validated for the measurement of AR symptoms and correlate well with the ARIA (allergic rhinitis and its impact on asthma) severity classification and also correlated well with rTNSS and RQLQ. Moreover, several treatment studies on AR have used VAS as an evaluation parameter. Thanks to the use of new (real-life and real-time) communication technologies, such as smartphone apps, Discussion: VAS can be used relatively simply and highly effectively to assess disease control. The VAS lends itself very well to digitization and has now been incorporated into a smartphone app (called Allergy Diary) to assess AR control and direct treatment decisions as part of an AR clinical decision support system (CDSS). MASK Rhinitis has developed this app, which is currently available in 15 different languages.
Numerous epidemiological studies have shown an inverse correlation between helminth infections and the manifestation of atopic diseases, yet the immunological mechanisms governing this phenomenon are indistinct. We therefore investigated the effects of infection with the filarial parasite Litomosoides sigmodontis on allergen-induced immune reactions and airway disease in a murine model of asthma. Infection with L. sigmodontis suppressed all aspects of the asthmatic phenotype: Ag-specific Ig production, airway reactivity to inhaled methacholine, and pulmonary eosinophilia. Similarly, Ag-specific recall proliferation and overall Th2 cytokine (IL-4, IL-5, and IL-3) production were significantly reduced after L. sigmodontis infection. Analysis of splenic mononuclear cells and mediastinal lymph nodes revealed a significant increase in the numbers of T cells with a regulatory phenotype in infected and sensitized mice compared with sensitized controls. Additionally, surface and intracellular staining for TGF-β on splenic CD4+ T cells as well as Ag-specific TGF-β secretion by splenic mononuclear cells was increased in infected and sensitized animals. Administration of Abs blocking TGF-β or depleting regulatory T cells in infected animals before allergen sensitization and challenges reversed the suppressive effect with regard to airway hyperreactivity, but did not affect airway inflammation. Despite the dissociate results of the blocking experiments, these data point toward an induction of regulatory T cells and enhanced secretion of the immunomodulatory cytokine TGF-β as one principle mechanism. In conclusion, our data support the epidemiological evidence and enhance the immunological understanding concerning the impact of helminth infections on atopic diseases thus providing new insights for the development of future studies.
To cite this article: Singh AK, Stock P, Akbari O. Role of PD‐L1 and PD‐L2 in allergic diseases and asthma. Allergy 2011; 66: 155–162. Abstract Asthma is the result of chronic airway inflammation associated predominantly with CD4+ cells, eosinophils, mast cells, and basophils. Several T‐cells subsets, including NKT cells, play a critical role in orchestrating the inflammation in the airways predominantly, by secreting interleukin‐4 and interleukin‐13. Recently, programmed death‐1 (PD‐1) with its ligands, programmed death ligand B7H1 (PD‐L1) and B7DC (PD‐L2), was shown to regulate T‐cell activation and tolerance. PD‐1 has been characterized as a negative regulator of conventional CD4+T cells. In addition, the relative roles of PD‐L1 and PD‐L2 in regulating the activation and function of T cells have recently been characterized. Recent studies have demonstrated that PD‐L1 and PD‐L2 have important but opposing roles in modulating and polarizing T‐cell functions in airway hyperreactivity. Whereas the severity of asthma is greatly enhanced in absence of PD‐L2, PD‐L1 deficiency resulted in reduced airway hyperresponsiveness and only minimal inflammation. This observation is partially because of the polarization of NKT cells in PD‐L1‐ and PD‐L2‐deficient mice. This review will discuss the recent literature regarding the role of PD‐L1 and PD‐L2 in allergic disease and asthma. Current understanding of the role of PD ligands in allergic asthma gives impetus to the development of novel therapeutic approaches.
IL-25 has been shown to induce Th2 responses and airway hyperreactivity (AHR) in mice, but the mechanism of action is not understood and it is unclear which cells mediate this disease. In this study we show that the receptor for IL-25, IL-17RB, is highly expressed on a subset of naive and activated CD4+ invariant NKT (iNKT) cells, but not on activated T cells. IL-17RB+ iNKT cells produced large amounts of Th2 cytokines that were substantially increased by IL-25 stimulation. Furthermore, IL-17RB+ iNKT cells were capable of restoring AHR in iNKT cell-deficient mice, whereas IL-17RB− iNKT cells failed to reconstitute AHR and lung inflammation. Finally, IL-17RB+ iNKT cells were detected in the lungs of wild-type mice, and induction of AHR by intranasal administration of IL-25 was significantly impaired in iNKT cell-deficient mice. Overall, our data suggest a critical role for iNKT cells in IL-25-mediated AHR. These results may lead to novel therapeutic approaches to target IL-17RB+ iNKT cells for the treatment of allergic asthma.
The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4− iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS−/− and ICOSL−/− mice, and the remaining iNKT cells in ICOS−/− mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jα18−/− mice. In addition, direct activation of iNKT cells with α-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS−/− mice. The failure of ICOS−/− iNKT cells to induce AHR was due in part to an inability of the ICOS−/− iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL−/− mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.
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