Biomedical subjects

Kurt Blaser

Publications and source records attributed to Kurt Blaser.

At least 19 recordsLinked to original sources

PubMed2006

TGF-beta1 in SP-A preparations influence immune suppressive properties of SP-A on human CD4+ T lymphocytes.

Surfactant protein A (SP-A) and transforming growth factor-beta1 (TGF-beta1) have been shown to modulate the functions of different immune cells and specifically to inhibit T lymphocyte proliferation. The aim of the present study was to elucidate whether the Smad signaling pathway, which is activated by TGF-beta1, also plays a role in SP-A-mediated inhibition of CD4+ T lymphocyte activation. Recombinant human SP-A1 expressed in Chinese hamster ovary cells [rSP-A1m (mammalian)], but not recombinant Baculovirus-derived rSP-A1hyp (hydroxyproline-deficient), suppressed T lymphocyte proliferation and IL-2 mRNA expression. To test whether SP-A induced Smad signaling, a Smad3/4-specific reporter gene was transfected in primary human CD4+ T lymphocytes. Only rSP-A1m, but not rSP-A1hyp, induced Smad-specific reporter genes, Smad2 phosphorylation, and Smad7 mRNA expression. The effect of rSP-A1m was mediated through the TGF-betaRII and could be antagonized by anti-TGF-beta1 neutralizing antibodies and sTGF-betaRII. Western blot and ELISA analysis revealed that rSP-A1m, but not rSP-A1hyp, contained TGF-beta1. TGF-beta1 was responsible for the differences in inhibition of CD4+ T lymphocyte proliferation and activation of the Smad signaling pathway between rSP-A1m and rSP-A1hyp. After acidification, native SP-A, obtained from patients with alveolar proteinosis, also induced Smad signaling in human CD4+ T lymphocytes leading to an increased inhibition of T lymphocyte proliferation, thus indicating the presence of inactive, latent TGF-beta1 in native SP-A samples. Association between SP-A and latent TGF-beta1 provides a possible novel mechanism to regulate TGF-beta1-mediated inflammation and fibrosis reactions in the lung but also leads to possible misinterpretation of immune-modulator functions of SP-A. Monitoring of SP-A preparations for possible TGF-beta1 is essential.

Acids↗

PubMed2006

Molecular mechanisms underlying FOXP3 induction in human T cells.

FOXP3 is playing an essential role for T regulatory cells and is involved in the molecular mechanisms controlling immune tolerance. Although the biological relevance of this transcription factor is well documented, the pathways responsible for its induction are still unclear. The current study reveals structure and function of the human FOXP3 promoter, revealing essential molecular mechanisms of its induction. The FOXP3 promoter was defined by RACE, cloned, and functionally analyzed using reporter-gene constructs in primary human T cells. The analysis revealed the basal, T cell-specific promoter with a TATA and CAAT box 6000 bp upstream the translation start site. The basal promoter contains six NF-AT and AP-1 binding sites, which are positively regulating the trans activation of the FOXP3 promoter after triggering of the TCR. The chromatin region containing the FOXP3 promoter was bound by NF-ATc2 under these conditions. Furthermore, FOXP3 expression was observed following TCR engagement. Promoter activity, mRNA, and protein expression of T cells were suppressed by addition of cyclosporin A. Taken together, this study reveals the structure of the human FOXP3 promoter and provides new insights in mechanisms of addressing T regulatory cell-inducing signals useful for promoting immune tolerance. Furthermore, the study identifies essential, positive regulators of the FOXP3 gene and highlights cyclosporin A as an inhibitor of FOXP3 expression contrasting other immunosuppressants such as steroids or rapamycin.

Animals↗

PubMed2006

Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26.

The family of IL-10-related cytokines includes several human members, IL-19, IL-20, IL-22, IL-24 and IL-26, and a series of herpesviral and poxviral paralogs. Some of these cytokines share common receptor subunits. In this study, we investigated the effects of these cytokines on naive T cell differentiation, antigen-specific T cell suppression, survival ad expression of surface markers in comparison to IL-10 and cytomegalovirus (CMV)-IL-10. Human CD45RA(+) T cells were stimulated in the presence of IL-10-family cytokines in sequential 12-day cycles. After three to four cycles of stimulation, IL-10 and CMV-IL-10 led to increased IFN-gamma and IL-10 but decreased IL-4 and IL-13. Interestingly, long-term exposure of T cells to IL-19, IL-20 and IL-22 down-regulated IFN-gamma but up-regulated IL-4 and IL-13 in T cells and supported the polarization of naive T cells to Th2-like cells. In contrast, neutralization of endogenous IL-22 activity by IL-22-binding protein decreased IL-4, IL-13 and IFN-gamma synthesis. The antigen-specific suppressor activity of IL-10 and CMV-IL-10 was not observed for any of the other IL-10-family cytokines. These data demonstrate that IL-19, IL-20 and IL-22 may participate in T cell-mediated diseases by distinct regulation of T cell cytokine profiles.

Cell Differentiation↗

PubMed2006

T-cell subsets in the pathogenesis of human asthma.

Genetic predisposition and environmental instructions tune thresholds for activation of T cells, other inflammatory cells, and resident tissue cells in asthmatic inflammation. Selective migration of peripheral-blood T cells to the lungs, their survival and reactivation in the submucosa, and their effector functions represent sequential immunologic events. Activation-induced T-cell death and peripheral T-cell tolerance are critical events in disease pathogenesis. As a mechanism for peripheral Th2 response in atopic diseases, particularly, the high interferon (IFN)-gamma-producing Th1 compartment of activated effector T cells shows increased activation-induced cell death, skewing the immune response toward surviving Th2 cells in allergic asthma. After migration to asthmatic lung, these cells switch on effector cytokines and induce bronchial epithelial apoptosis with mainly IFN-gamma, tumor necrosis factor (TNF)-alpha, and Fas-ligand. In addition, skewing of allergen-specific effector T cells to T-regulatory cells appears to be an essential event in the control of harmful immune response induced by allergens as a possible means for remedy.

Allergens↗

PubMed2006

Histamine receptors in immune regulation and allergen-specific immunotherapy.

The cells involved in the regulation of immune responses and hematopoiesis express histamine receptors and secrete histamine. Histamine acting through four types of its receptors has been shown not only to affect chronic inflammatory responses but also to regulate several essential events in the immune response. Histamine signals have a role in the mechanisms of tolerance induced during allergen-specific immunotherapy (SIT), acting mainly through its receptor (HR) type 2. It positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. The rationale for the concomitant use of H1 antihistamines during SIT is diverse and includes reduction of its immediate side effects as well as enhancement of mechanisms of specific tolerance and anti-inflammatory effects of vaccination.

Allergens↗

PubMed2006

Mechanisms of allergen-specific immunotherapy: T-regulatory cells and more.

Activation-induced cell death, anergy, or immune response modulation by regulatory T cells (Treg cells) are essential mechanisms of peripheral T-cell tolerance. Genetic predisposition and environmental instructions tune thresholds for the activation of T cells, other inflammatory cells, and resident tissue cells in allergic diseases. Skewing allergen-specific effector T cells to a Treg-cell phenotype seems to be crucial in maintaining a healthy immune response to allergens and successful allergen-specific immunotherapy. The Treg-cell response is characterized by an abolished allergen-specific T-cell proliferation and the suppressed secretion of T-helper 1- and T-helper 2-type cytokines. Suppressed proliferative and cytokine responses against allergens are induced by multiple suppressor factors, including cytokines such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta), and cell surface molecules such as cytotoxic T-lymphocyte antigen-4, programmed death-1, and histamine receptor 2. The increased levels of IL-10 and TGF-beta produced by Treg cells potently suppress IgE production while simultaneously increasing the production of noninflammatory isotypes IgG4 and IgA, respectively. In addition, Treg cells directly or indirectly suppress the activity of effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils. In conclusion, peripheral tolerance to allergens is controlled by multiple active suppression mechanisms on T cells, regulation of antibody isotypes, and suppression of effector cells. The application of current knowledge of Treg cells and related mechanisms of peripheral tolerance may soon lead to more rational and safer approaches to the prevention and cure of allergic disease.

Allergens↗

PubMed2006

The role of TGF-beta in allergic inflammation.

The transforming growth factor beta (TGF-beta) plays a dual role in allergic disease. It is important in suppressing T cells and also mediates repair responses that lead to unwanted remodeling of tissues. Advances in the immunology of allergy indicate that allergens cause overreactions in the lymphocyte compartment because of the lack or decreased number of suppressive, regulatory T cells. TGF-beta was shown to induce regulatory T cells and participate directly in suppression of effector T cells. Therefore, TGF-beta may help return reactivity to allergens to normal subsymptomatic activity. Whether chronic inflammatory diseases such as asthma profit from TGF-beta-mediated suppression of specific immune responses or whether the TGF-beta-mediated tissue remodeling aggravates diseases more than it helps control immune reactions is unclear. This article addresses these issues and future strategies in this field.

Humans↗

PubMed2006

Absence of T-regulatory cell expression and function in atopic dermatitis skin.

BACKGROUND: The role of regulatory T cells has been widely reported in the suppression of T-cell activation. A dysfunction in CD4(+)CD25(+) T-regulatory cell-specific transcription factor FoxP3 leads to immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome, often associated with atopic dermatitis. Increasing the number and activity of regulatory T cells in affected organs has been suggested as a remedy in various inflammatory diseases, including allergy. OBJECTIVE: To determine the presence and function of regulatory T cells in atopic dermatitis. METHODS: Immunohistochemistry of lesional atopic dermatitis skin and control skin conditions was used to demonstrate regulatory cells and cytokines in situ. The role of effector and regulatory T cells as well as their specific cytokines in apoptosis in human keratinocyte cultures and artificial skin equivalents was investigated. RESULTS: Human T-regulatory type 1 cells, their suppressive cytokines, IL-10 and TGF-beta, as well as receptors for these cytokines were significantly expressed, whereas CD4(+)CD25(+)FoxP3(+) T-regulatory cells were not found in lesional and atopy patch test atopic dermatitis or psoriasis skin. Both subsets of regulatory T cells suppress the allergen-specific activation of T(H)1 and T(H)2 cells. In coculture and artificial skin equivalent experiments, subsets of T-regulatory cells neither induced keratinocyte death nor suppressed apoptosis induced by skin T cells, T(H)1 cells, IFN-gamma, or TNF-alpha. CONCLUSION: A dysregulation of disease-causing effector T cells is observed in atopic dermatitis lesions, in association with an impaired CD4(+)CD25(+)FoxP3(+) T-cell infiltration, despite the expression of type 1 regulatory cells in the dermis.

Adult↗

PubMed2006

Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific interleukin-4 (IL-4)-secreting T cells in allergic individuals. Allergen-specific immunotherapy can induce specific Tr1 cells that abolish allergen-induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL-10 and transforming growth factor-beta (TGF-beta) as secreted cytokines and various surface molecules, such as cytotoxic T-lymphocyte antigen 4 and programmed death-1. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors, which depend on CD28 costimulation. IL-10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3-kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL-10 and TGF-beta secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non-inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen-specific Tr1 cells can thus re-direct an inappropriate immune response against allergens or auto-antigens using a broad range of suppressor mechanisms.

Allergens↗

PubMed2006

T regulatory cells in allergy.

Activation-induced cell death, anergy and/or immune response modulation by T regulatory cells (T(Reg)) are essential mechanisms of peripheral T-cell tolerance. There is growing evidence that anergy, tolerance and active suppression are not entirely distinct, but rather, represent linked mechanisms possibly involving the same cells and multiple suppressor mechanisms. Skewing of allergen-specific effector T cells to T(Reg) cells appears as a crucial event in the control of healthy immune response to allergens and successful allergen-specific immunotherapy. The T(Reg) cell response is characterized by abolished allergen-induced specific T-cell proliferation and suppressed T helper 1 (Th1)- and Th2-type cytokine secretion. The increased levels of interleukin-10 (IL-10) and transforming growth factor-Beta (TGF-Beta) that are produced by T(Reg) cells, potently suppress IgE production, while simultaneously increasing production of noninflammatory isotypes IgG4 and IgA, respectively. In addition, T(Reg) cells directly or indirectly suppress effector cells of allergic inflammation such as mast cells, basophils, and eosinophils. In conclusion, peripheral tolerance to allergens is controlled by multiple active suppression mechanisms. It is associated with regulation of antibody isotypes and effector cells to the direction of a healthy immune response and opens a window for novel therapies of allergic diseases.

Animals↗

PubMed2006

The role of histamine in regulation of immune responses.

Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. It can influence numerous functions of the cells involved in the regulation of immune response and hematopoiesis including macrophages, dendritic cells, T lymphocytes, B lymphocytes and endothelial cells. These cells express histamine receptors and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions leading to chronic inflammation. Histamine regulates antigen-specific Th1 and Th2 cells, as well as related antibody isotype responses. Histamine acting through its receptor (HR) type 2, positively interferes with the peripheral antigen tolerance induced by T regulatory (T(Reg)) cells in several pathways. The diverse effects of histamine on immune regulation are due to differential expression and regulation of 4 histamine receptors and their distinct intracellular signals. In addition, differences in affinities of these receptors are highly decisive on the biological effects of histamine and agents that target histamine receptors. Although substantial evidence has been accumulated about histamine metabolism, receptors, signal transduction, physiological and pathological effects, the complex interrelationship and cross-talk by histamine, its receptors and other G-protein coupled receptors remain to be understood.

Animals↗

PubMed2006

Mechanisms of allergen-specific immunotherapy.

Allergen-specific immunotherapy (SIT) is the only treatment, which leads to a life-long tolerance against allergens due to restoration of normal immunity. The induction of a tolerant state in peripheral T cells represents an essential step in allergen-SIT. Peripheral T-cell tolerance is characterized mainly by suppressed proliferative and cytokine responses against the major allergens and its T-cell recognition sites. It is initiated by autocrine action of IL-10 and/or TGF-Beta, which are increasingly produced by the antigen-specific T Regulatory (T(Reg)) cells. Tolerized T cells can be reactivated to produce either of the distinct Th1 or Th2 cytokine patterns, thus directing allergen-SIT towards successful or unsuccessful treatment. T(Reg) cells directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. In addition, there is accumulating evidence that they may suppress IgE production and induce IgG4 and IgA production against allergens. By the application of the recent knowledge in mechanisms of allergen-SIT, more rational and safer approaches are awaiting in the future for the prevention and cure of allergic diseases.

Allergens↗

PubMed2006

Immunological mechanisms of specific allergen immunotherapy.

Allergy is an immunological disorder, which is driven by uncontrolled allergen-activated T cell subsets, leading to immediate type hypersensitivity against otherwise harmless environmental allergens. These allergens are tolerated by healthy individuals as well as by patients, who successfully underwent allergen-specific immunotherapy (SIT). The successful SIT is characterized by the induction of T cell unresponsiveness against the given allergen. Regulatory T cells (Tregs), which are installed or enhanced by SIT and govern the activity of potentially pro-allergic effector T cells, mediate this unresponsiveness. The current article reviews the mechanisms underlying the balance of these cell populations along with suppressive mechanisms of SIT, which may serve as future drug targets.

Allergens↗

PubMed2005

Activin A is an acute allergen-responsive cytokine and provides a link to TGF-beta-mediated airway remodeling in asthma.

BACKGROUND: Allergic asthma typically shows activated, allergen-specific CD4(+) T cells in the early phase and airway remodeling in the late phase of the disease. Although TGF-beta plays a crucial role in airway remodeling, it is only marginally induced in CD4(+) T cells in the early allergen-dependent activation of the immune system. OBJECTIVE: To elucidate the transition between early- and late-phase events, we investigated the role of activin A, a close family member of TGF-beta. METHODS: Activin A and TGF-beta(1) levels were measured systemically in the serum and in CD4(+) T cells of asthmatic patients, as well as locally in the lung. RESULTS: Activin A serum levels were increased in patients with severe asthma compared with levels in patients with moderate asthma and healthy control subjects, whereas all patients showed significantly increased TGF-beta(1) serum levels independent of disease severity. In T cells only patients with moderate asthma showed increased activin A mRNA expression, whereas TGF-beta(1) expression was equal to that seen in healthy subjects. Accordingly, ovalbumin sensitization in a mouse model of allergic asthma could induce activin A mRNA expression, but not TGF-beta(1) expression, in the lung. Immunohistochemistry of mice and human specimens revealed an abundant expression of activin A by infiltrating lymphocytes and structural cells of the lung. Although TGF-beta(1) more potently enhanced proliferation and Smad 2/3-dependent reporter genes in fibroblasts, activin A was capable of inducing TGF-beta(1) and vice versa. CONCLUSION: Activin A provides a link between acute allergen-specific T-cell responses and chronic TGF-beta(1)-mediated airway remodeling in asthma.

Activins↗

PubMed2005

T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases.

The identification of T regulatory (T(Reg)) cells as key regulators of immunologic processes in peripheral tolerance to allergens has opened an important era in the prevention and treatment of allergic diseases. Both naturally occurring CD4(+)CD25(+) T(Reg) cells and inducible populations of allergen-specific IL-10-secreting T(R)1 cells inhibit allergen-specific effector cells in experimental models. Allergen-specific T(Reg) cell responses contribute to the control of allergic inflammation in several ways. Skewing of allergen-specific effector T cells to a T(Reg) phenotype appears to be a crucial event in the development of a healthy immune response to allergens and successful outcome in allergen-specific immunotherapy. The increased levels of IL-10 and TGF-beta produced by T(Reg) cells can potently suppress IgE production while simultaneously increasing the production of the noninflammatory antibody isotypes IgG4 and IgA, respectively. T(Reg) cells directly or indirectly suppress effector cells of allergic inflammation, such as mast cells, basophils, and eosinophils, and contribute to remodeling in asthma and atopic dermatitis. In addition, mediators of allergic inflammation that trigger cyclic AMP-associated G protein-coupled receptors, such as histamine receptor 2, might play a role in peripheral tolerance mechanisms against allergens. Current strategies for drug development and allergen-specific immunotherapy exploit these observations with the potential to provide cure for allergic diseases.

Animals↗

PubMed2005

Apoptosis and loss of adhesion of bronchial epithelial cells in asthma.

BACKGROUND: Asthma is an inflammatory airway disease associated with infiltration of T cells and eosinophils, increased levels of pro-inflammatory cytokines, and shedding of bronchial epithelial cells (EC). We have recently shown that T cells and eosinophils cooperate in inducing bronchial EC apoptosis in asthma through secretion of IFN-gamma and TNF-alpha. Since EC shedding is a histologic hallmark of asthma, the intercellular junction of EC may be a target of pro-inflammatory cytokines. METHODS: Bronchial EC, cultured and exposed to IFN-gamma and TNF-alpha, were studied for the expression of adhesion molecules and apoptosis. In addition, the epithelial layer of bronchial biopsies from asthma patients was evaluated for apoptosis, shedding, and expression of adhesion molecules. RESULTS: We demonstrate that the induction of EC apoptosis is accompanied by loss of E-cadherin. In situ examination of E-cadherin in asthma revealed a reduction in its expression on EC membranes. In contrast, the in vitro and in vivo expression of beta1-integrins and intercellular adhesion molecule-1 (ICAM-1) increased on EC during asthmatic airway inflammation. CONCLUSIONS: Loss of cadherin-mediated intercellular adhesion and apoptosis could account for fragility and shedding of EC in asthma, especially since this occurs between columnar and basal EC.

Apoptosis↗

PubMed2005

TGF-{beta} signaling of human T cells is modulated by the ancillary TGF-{beta} receptor endoglin.

Transforming growth factor beta (TGF-beta) inhibits T cell activation and alters differentiation of naive T cells into effector cells. Although four main cell-surface proteins can interact with TGF-beta, only the signaling receptors type I (TGF-betaR type I) and type II (TGF-betaR type II) have so far been described on T cells. The aim of the present study was to investigate the expression of the ancillary receptor endoglin (CD105) by T cells and its role in TGF-beta-mediated signal transduction and function. CD105 expression was analyzed on resting and activated human CD4(+) T cells by flow cytometry, western blot, immunoprecipitation, proliferation and SMAD-responsive reporter gene assays. CD4(+) T cells constitutively expressed CD105 in memory T cells and partially also in naive T cells; however, surface expression is regulated and is increased following TCR engagement, which induced serine/threonine phosphorylation of CD105. In contrast to the suppressive signal mediated by the TGF-beta, cross-linking of CD105 substantially enhanced T cell proliferation, indicating that CD105 by itself mediates signal transduction. Furthermore, CD105 cross-linking induced SMAD-independent signaling via ERK kinase phosphorylation. The present study demonstrates that CD105 is expressed on the surface by activated CD4(+) T cells and CD3 regulated by post-translational means. Furthermore, CD105 acts as a regulatory receptor, counteracting TGF-beta-mediated suppression.

Activin Receptors, Type I↗

PubMed2005

Histamine in allergic inflammation and immune modulation.

Histamine, originally considered as a mediator of acute inflammatory and immediate hypersensitivity responses has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. On the other hand, various cytokines control histamine synthesis, release and expression of histamine receptors (HRs). The cells involved in the regulation of immune response and hematopoiesis express HRs and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization and effector functions leading to chronic inflammation. Histamine, acting through its receptor type 2, positively interferes with the peripheral antigen tolerance induced by T regulatory cells in several pathways. Histamine also regulates antigen-specific Th1 and Th2 cells, as well as related antibody isotype responses. The diverse effects of histamine on immune regulation are due to differential expression and regulation of four HRs and their distinct intracellular signals. In addition, differences in affinities of these receptors are highly decisive on the biological effects of histamine and agents that target HRs. This article highlights the findings leading to a change of perspective in histamine immunobiology.

Histamine↗