Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation

It was demonstrated 5 years ago that thymic stromal lymphopoietin (TSLP), a IL-7-like cytokine produced by epithelial cells, could strongly activate human myeloid dendritic cells to induce an inflammatory T(H)2 response characterized by high TNF-alpha and little IL-10 production, distinct from the regulatory T(H)2 responses characterized by low TNF-alpha and high IL-10 production. TSLP was found highly expressed by keratinocytes of skin lesions of atopic dermatitis and associated with dendritic cell activation in situ. This suggests for the first time that TSLP represents a master switch of allergic inflammation at the epithelial cell and dendritic cell interface. During the last several years, the evidence for the association of TSLP with human asthma was revealed. The direct link between TSLP expression with the pathogenesis of atopic dermatitis and asthma in vivo was demonstrated. In addition, OX40 ligand was found to be the TSLP-induced molecule on dendritic cells that triggers inflammatory T(H)2 differentiation in the absence of IL-12. TSLP was also demonstrated to direct the innate phase of allergic immune responses through activating mast cells. Therefore, TSLP and OX40 ligand may represent important targets for intervention of the initiation of allergic inflammatory responses.     

胸腺基质淋巴细胞生成素、OX40和OX40受体在过敏性腹泻小鼠大肠黏膜中表达的关系

目的 建立小鼠过敏性腹泻模型,检测其大肠黏膜中胸腺基质淋巴细胞生成素(TSLP)、OX40、OX40受体(OX40L)的表达和肠系膜淋巴结细胞培养上清中IL-4、IFN-γ的水平,分析其之间的关系,探讨TSLP、OX40、OX40L在过敏性腹泻中的作用.方法 雌性BALB/c小鼠20只随机分成两组即对照组和实验组.采用酶联免疫吸附法(ELISA)检测肠系膜淋巴结细胞培养上清中IL-4和IFN-γ的水平,取大肠组织HE染色观察大肠组织病理改变,SP免疫组织化学技术检测TSLP、OX40、OX40L的表达.结果 ①HE染色结果显示:实验组比对照组小鼠结肠黏膜组织非特异性炎症反应显著,上皮排列不规则,有大量炎性细胞浸润,固有层可见大量嗜酸性粒细胞浸润;②TSLP、OX40、OX40L在过敏性腹泻小鼠大肠黏膜中的表达水平高于对照组的表达水平(t=7.07,t =7.81,t =7.79,P均＜0.01);③Spearman等级相关分析发现TSLP、OX40、0X40L三者间表达强度存在正相关(r=0.889,r=0.932,r=0.943,P均＜0.01),同时三者与肠系膜淋巴结细胞培养上清中IL-4水平呈正相关(r=0.891,r =0.936,r=0.886,P均＜0.05),而与IFN-γ水平呈负相关(r=-0.829,r=-0.881,r=-0.937,P均＜0.05).结论 TSLP、OX40、OX40L三者间表达存在正相关,并诱导了Th1/Th2轴向Th2轴漂移,促进了过敏性腹泻的发生发展.     

人胸腺基质淋巴细胞生成素与过敏性疾病的研究进展

人胸腺基质淋巴细胞生成素（TSLP）是新近发现的具有IL-7样功能的细胞因子。它能够强烈诱导DC表达MHCⅡ类分子以及协同刺激分子CD40、CD80，促进DC产生招募Th2型细胞的趋化因子CCL17和CCL22，诱导初始T细胞分化为分泌IL-4、IL-5、IL-13的变应原特异性CD^4和CD8^＋效应T细胞，调节机体免疫应答向Th2型偏移，从而参与遗传过敏性皮炎、哮喘等多种过敏性疾病的发生过程。     

Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow-derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell-attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.     

Thymic stromal lymphopoietin and the pathophysiology of atopic disease

Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine expressed predominantly by barrier epithelial cells. TSLP is a potent activator of several cell types, including myeloid-derived dendritic cells, monocytes/macrophages and mast cells. Recent studies have revealed an important role for TSLP in the initiation and progression of allergic inflammatory diseases. In this review, we will discuss the role of TSLP in atopic diseases, as well as its function in immune homeostasis.     

Thymic stromal lymphopoietin in normal and pathogenic T cell development and function

Thymic stromal lymphopoietin, a four helix-bundle cytokine, is expressed mainly by barrier epithelial cells and is a potent activator of several cell types, particularly myeloid dendritic cells. TSLP influences the outcome of interactions between dendritic cells and CD4+ thymocytes and T cells in many situations, such as the regulation of the positive selection of regulatory T cells, maintenance of peripheral CD4+ T cell homeostasis and induction of CD4+ T cell-mediated allergic inflammation.     

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

Both thymic stromal lymphopoietin (TSLP) and IL‐13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL‐13 has not yet been fully elucidated. This study aimed to investigate whether IL‐13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL‐13 induced TSLP expression in mouse nasal tissue specimens in a Stat6‐dependent manner. In addition, intranasal challenge of mice with IL‐13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL‐13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti‐TSLP Ab. These findings suggest that TSLP is an important mediator of IL‐13‐driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL‐13 is a critical downstream element for TSLP‐driven allergic inflammation, TSLP may function both upstream and downstream of IL‐13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.     

CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction

T regulatory (Treg) cells play a role in the suppression of immune responses, thus serving to induce tolerance and control autoimmunity. Here, we explored whether Treg cells influence the immediate hypersensitivity response of mast cells (MCs). Treg cells directly inhibited the FcvarepsilonRI-dependent MC degranulation through cell-cell contact involving OX40-OX40L interactions between Treg cells and MCs, respectively. When activated in the presence of Treg cells, MCs showed increased cyclic adenosine monophosphate (cAMP) concentrations and reduced Ca(2+) influx, independently of phospholipase C (PLC)-gamma2 or Ca(2+) release from intracellular stores. Antagonism of cAMP in MCs reversed the inhibitory effects of Treg cells, restoring normal Ca(2+) responses and degranulation. Importantly, the in vivo depletion or inactivation of Treg cells caused enhancement of the anaphylactic response. The demonstrated crosstalk between Treg cells and MCs defines a previously unrecognized mechanism controlling MC degranulation. Loss of this interaction may contribute to the severity of allergic responses.     

Thymic stromal lymphopoietin plays an adjuvant role in BCG-mediated CD8 cytotoxic T cell responses through dendritic cell activation

Although Bacillus Calmette–Guérin (BCG) has historically emerged as a potent adjuvant in cancer immunization through dendritic cell (DC) activation, the efficacy of its antitumor effect has been limited. Therefore, the strategy of adjuvant therapy using BCG needs to be improved by adding enhancers. Here we found that thymic stromal lymphopoietin (TSLP) acts as an enhancer for the BCG-mediated antitumor effect. While BCG-stimulated DCs induced CD8⁺ T cell production of IFN-γ without strong cell expansion, TSLP-stimulated DCs induced robust CD8⁺ T cell expansion without high quantities of IFN-γ production. Notably, DCs stimulated with both BCG and TSLP induced robust expansion of CD8⁺ T cells that produced a large amount of IFN-γ with a potent cytolytic activity related to granzyme B expression. Our data suggest that TSLP is a good adjuvant to enhance the BCG-mediated cytotoxic T cell effect through DC activation, and provide a functional basis for a novel strategy for antitumor immune-based therapy.     

Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma

Individuals with one atopic disease are far more likely to develop a second. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. This association, suggesting a role for AD as an entry point for subsequent allergic disease, is a phenomenon known as the "atopic march." Although the underlying cause of the atopic march remains unknown, recent evidence suggests a role for the cytokine thymic stromal lymphopoietin (TSLP). We have established a mouse model to determine whether TSLP plays a role in this phenomenon, and in this study show that mice exposed to the antigen ovalbumin (OVA) in the skin in the presence of TSLP develop severe airway inflammation when later challenged with the same antigen in the lung. Interestingly, neither TSLP production in the lung nor circulating TSLP is required to aggravate the asthma that was induced upon subsequent antigen challenge. However, CD4 T cells are required in the challenge phase of the response, as was challenge with the sensitizing antigen, demonstrating that the response was antigen specific. This study, which provides a clean mouse model to study human atopic march, indicates that skin-derived TSLP may represent an important factor that triggers progression from AD to asthma.     

Thymic stromal lymphopoietin (TSLP) as a bridge between infection and atopy

The rising worldwide prevalence of asthma has intensified interest in the natural history of asthma. An improved understanding of the genetic, environmental, and developmental factors contributing to the inception and exacerbation of asthma will be crucial to efforts to devise effective preventive and therapeutic interventions. There is increasing evidence that the complex interplay of early life respiratory viral infections and allergic sensitization is important in the development of asthma. Major causes of asthma exacerbations are respiratory viral infections and aeroallergen exposure, which may have interactive co-morbid effects. This review describes the potential role of thymic stromal lymphopoietin (TSLP) as a connection between the innate immune response to respiratory viral infections and the type-2 adaptive immune response in the development and exacerbation of asthma.     

OX40 blockade inhibits house dust mite driven allergic lung inflammation in mice and in vitro allergic responses in humans

The costimulatory receptor OX40 is expressed on activated T cells and regulates T‐cell responses. Here, we show the efficacy and mechanism of action of an OX40 blocking antibody using the chronic house dust mite (HDM) mouse model of lung inflammation and in vitro HDM stimulation of cells from HDM allergic human donors. We have demonstrated that OX40 blockade leads to a reduction in the number of eosinophils and neutrophils in the lavage fluid and lung tissue of HDM sensitized mice. This was accompanied by a decrease in activated and memory CD4⁺ T cells in the lungs and further analysis revealed that both the Th2 and Th17 populations were inhibited. Improved lung function and decreased HDM‐specific antibody responses were also noted. Significantly, efficacy was observed even when anti‐OX40 treatment was delayed until after inflammation was established. OX40 blockade also inhibited the release of the Th2 cytokines IL‐5 and IL‐13 from cells isolated from HDM allergic human donors. Altogether, our data provide evidence of a role of the OX40/OX40L pathway in ongoing allergic lung inflammation and support clinical studies of a blocking OX40 antibody in Th2 high severe asthma patients.