Die Rolle regulatorischer T-Zellen im experimentellen allergischen Asthma

Im ersten Teil der Dissertation wurde in einem experimentellen Asthmamodell demonstriert, dass die Signaltransduktion über IL-6 das Gleichgewicht zwischen Effektorzellen und regulatorischen T-Zellen durch verschiedene Rezeptorkomponenten kontrolliert. Hierbei zeigte sich, dass speziell das IL-6 Trans-Signaling über den sIL-6R die TH2 Cytokinproduktion steuert. Dagegen führt die Blockade des mIL-6R zur Expansion regulatorischer T-Zellen mit suppressiven Eigenschaften. Diese CD4+CD25+ Tregs induzieren außerdem IFN gamma produzierende CD4+ T-Zellen in der Lunge und verbessern daneben die AHR. Im Überblick konnte in der vorliegenden Dissertation demonstriert werden, dass IL-6 die Balance zwischen der Funktion von Effektorzellen und regulatorischen T-Zellen in der Lunge über unterschiedliche Wege kontrolliert, dem sIL-6R und dem mIL-6R. Im zweiten Teil der Arbeit wurde die lokale Blockade der IL-2R alpha- und IL-2R beta-Kette untersucht. Hier konnte gezeigt werden, dass die Blockade der IL-2R beta-Kette zur Verbesserung der AHR als auch der Rekrutierung eosinophiler Granulozyten in den Atemwegen führt. Beide Blockaden führen zur Reduktion der TH2 Cytokine IL-4 und IL-5, wohingegen IL-13 nur nach Blockade der IL-2R beta-Kette vermindert sezerniert wird. In diesem Zusammenhang wurde auch die Rolle CD4+CD25+ regulatorischer T-Zellen untersucht, wobei eine Induktion dieser Population in den Lymphknoten nach Blockade der IL-2R beta-Kette nachgewiesen werden konnte. Die Blockade der IL-2R beta-Kette wirkt sich positiv auf experimentelle Asthmastudien aus und stellt somit ein mögliches therapeutisches Potential dar, erfordert aber teilweise noch weitere Untersuchungen.To assess the role of IL-6 signal transduction in experimental asthma the effect of intranasal blockade of the sIL-6R or the mIL-6R and sIL-6R were compared. The inhibition of IL-6 signaling results in beneficial effects by simultaneously suppressing TH2 cell development via sIL-6R signaling and skewing naive CD4+ cells to a Th1 pathway and/or expanding Tregs via mIL-6R signaling. In summary, IL-6 signaling in the lung tightly controls the critical balance between effector and Treg function via differential signaling events involving sIL-6R and mIL-6R, respectively. In a further study the effect of intranasal blockade of the IL-2R alpha- or IL-2R beta-chains were compared. The local blockade of the IL-2R beta-chain led to an amelioration of airway resistance and inflammation in OVA sensitized and challenged mice. Moreover, both treatments led to a marked reduction of the TH2 type cytokines IL-4 and IL-5, while IL-13 was inhibited specifically by the blockade of the IL-2R beta-chain. Consistent with these findings, the blockade of the IL-2R beta-chain, as opposed to the blockade of the IL-2R alpha chain, led to suppression of CD4+ T cell proliferation in the local draining lymph nodes where immunosuppressive CD4+CD25+ T regulatory cells were downregulated specifically by the local IL-2R alpha blockade. Taken together, these results suggest that the local blockade of the IL-2R beta-chain during the antigen challenge phase could be a successful therapy in allergic disease by rescuing the T regulatory cells in the local draining lymph nodes where they regulate the development of pathogenic TH2 cells in this experimental model of asthma

Mucosal immunoregulation : transcription factors as possible therapeutic targets

Much progress has been recently made with regard to our understanding of the mucosal immune system in health and disease. In particular, it has been shown that uncontrolled mucosal immune responses driven by lymphocytes or non-lymphoid cells may lead to immunological diseases such as allergy, hypersensitivity and inflammation. Thus, a more detailed understanding of mucosal immune regulation and decision making at mucosal surfaces is essential for a better understanding of mucosal immune responses in health and disease. Antigen presenting cells and T lymphocytes play a key role in controlling mucosal immune responses. To deal with this key task, T helper cells differentiate into functionally distinct subsets: TH1 (CD4 T Helper cells), TH2, TH3, Tr1, and CD4 CD25 T (Treg) cells. This review summarizes the role of antigen presenting cells, eosinophils, mast cells and T-cell subsets in the pathogenesis of allergic inflammation and intestinal inflammation. Furthermore, we discuss novel immunological treatment modalities for allergic inflammation (e.g. allergic asthma) and chronic intestinal inflammation (e.g. inflammatory bowel diseases (IBD)) such as the control of the expression of transcription factors to redirect pathological immune responses

Additional file 3: of Dendritic cells change IL-27 production pattern during childhood

Figure S3. Age-related cell frequency

Additional file 4: of Dendritic cells change IL-27 production pattern during childhood

Figure S4. Age related frequencies of IL-27-positive mDCs (top row) and pDCs (lower row)

Local blockade of IL-6R signaling induces lung CD4 T cell apoptosis in a murine model of asthma via regulatory T cells

We previously reported high levels of the soluble form of the IL-6R (sIL-6R) in the airways of asthmatic subjects. Here, we analyzed the IL-6R effects on T(h)2 cell survival in the lung by locally antagonizing sIL-6R-mediated trans-signaling with a designer fusion protein (gp130-Fc) as well as IL-6R signaling with an antibody against the gp80 unit of the IL-6R (alpha IL-6R) in a murine model of asthma after ovalbumin peptide (OVA) sensitization and challenge. Blockade of the sIL-6R led to a significant decrease in inflammatory cells by an apoptosis-independent mechanism. In contrast, local treatment with aIL-6R antibodies that also block signaling via the membrane-bound IL-6R (mIL-6R) led to decreased signal transducers and activators of transcription (STAT)-3 but not STAT-1 phosphorylation in the lung of treated mice as compared with control-treated mice. Moreover, this treatment induced apoptosis of the cells present in the airways of OVA-treated mice as well as apoptosis of lung CD4 effector T cells. Subsequent studies showed that this effect was mediated by lung CD4 CD25 Foxp3 T regulatory cells by a cell-cell interaction, thereby contributing to the resolution of airway hyperresponsiveness in OVA-treated mice given anti-IL-6R antibodies. Taken together, these data suggest that blockade of mIL-6R signaling leads to cell death of lung effector T cells by activating regulatory T cells in experimental asthma. Local targeting of IL-6R signaling could be a novel approach for inducing T,,2 T cell death in allergic airways via regulatory T cells

Enhanced in Vivo Targeting of Murine Nonparenchymal Liver Cells with Monophosphoryl Lipid A Functionalized Microcapsules

A broad spectrum of infectious liver diseases emphasizes the need of microparticles for targeted delivery of immunomodulatory substances to the liver. Microcapsules (MCs) are particularly attractive for innovative drug and vaccine formulations, enabling the combination of antigen, drugs, and adjuvants. The present study aimed to develop microcapsules characterized by an enhanced liver deposition and accelerated uptake by nonparenchymal liver cells (NPCs). Initially, two formulations of biodegradable microcapsules were synthesized from either hydroxyethyl starch (HES) or mannose. Notably, HES-MCs accumulated primarily in the liver, while mannose particles displayed a lung preference. Functionalization of HES-MCs with anti-CD40, anti-DEC205, and/or monophosphoryl lipid A (MPLA) enhanced uptake of MCs by nonparenchymal liver cells in vitro. In contrast, only MPLA-coated HES-MCs promoted significantly the in vivo uptake by NPCs. Finally, HES-MCs equipped with MPLA, anti-CD40, and anti-DEC205 induced the secretion of TNF-α, IL-6 by Kupffer cells (KCs), and IFN-γ and IL-12p70 by liver dendritic cells (DCs). The enhanced uptake and activation of KCs by MPLA-HES-MCs is a promising approach to prevent or treat infection, since KCs are exploited as an entry gate in various infectious diseases, such as malaria. In parallel, loading and activating liver DCs, usually prone to tolerance, bears the potential to induce antigen specific, intrahepatic immune responses necessary to prevent and treat infections affecting the liver