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Edgar Schmitt

Publications and source records attributed to Edgar Schmitt.

31 records · Page 2Linked to original sources
PubMed2004

Susceptibility to collagen-induced arthritis is modulated by TGFbeta responsiveness of T cells.

The objective of our study was to determine the regulatory effects that endogenous transforming growth factor beta (TGFbeta) exerts on T cells in the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in transgenic mice expressing a dominant negative TGFbeta type II receptor in T cells under the control of the human CD2 promoter. Clinical and histological arthritis scores were determined and experiments on disease induction and the healing phase of disease were performed. The proliferation and cytokine production of draining lymph node cells in vitro were analyzed. Transgenic mice were more susceptible to induction of CIA. The overall incidence was higher in transgenic mice than in wild-type mice (57% vs 35%, P < 0.05). Affected transgenic animals displayed a significantly higher clinical (4.5 +/- 0.6 vs 1.67 +/- 0.19, P = 0.001) and histological arthritis score (8.01 +/- 0.9 vs 4.06 +/- 1.1, P < 0.05). Draining lymph node cells of transgenic mice secreted more tumor necrosis factor alpha and IFNgamma and proliferated more vigorously in response to collagen type II and upon CD3/CD28 costimulation in vitro. Therefore, the regulation of T cells by endogenous TGFbeta is important for the maintenance of joint integrity after arthritis induction. Defects in TGFbeta-signalling as a susceptibility factor for rheumatoid arthritis may warrant further investigation.

Animals↗
PubMed2004

Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells.

Down-regulation of autoreactive T cell responses in vivo includes cell-contact-dependent as well as contact-independent mechanisms. Infectious tolerance is a contact-dependent mechanism used by naturally occurring CD25(+) T regulatory cells (Tregs) to confer suppressive activity upon conventional CD4(+) T cells thereby generating secondary T helper suppressor cells(Th(sup)), which inhibit T cell activation via soluble mediators. Here, we describe two distinct subsets of human Tregs, characterized by expression of either the alpha(4)beta(7) integrin or the alpha(4)beta(1) integrin. Upon activation, both subsets show an enhanced expression of FoxP3, recently described as a key transcription factor of murine Tregs. In addition, both are able to convey suppressive capacity to conventional CD4(+) T cells. However, the properties of Treg subsets are rather distinct: alpha(4)beta(7) (+)Tregs induce IL-10-producing Th(sup) (Tr1-like), whereas alpha(4)beta(1) (+) Tregs induce TGF-beta-producing Th(sup) (Th3-like). Our findings reconcile conflicting results by clearly demonstrating that suppression through naturally occurring CD25(+) Tregs is primary cell-contact-dependent but is subsequently followed by cell-contact-independent T cell inhibition mediated by second-generation Tr1- and Th3-like Th(sup) via the soluble factors IL-10 and TGF-beta.

Humans↗
PubMed2003

Influenza A virus infection inhibits the efficient recruitment of Th2 cells into the airways and the development of airway eosinophilia.

Most infections with respiratory viruses induce Th1 responses characterized by the generation of Th1 and CD8(+) T cells secreting IFN-gamma, which in turn have been shown to inhibit the development of Th2 cells. Therefore, it could be expected that respiratory viral infections mediate protection against asthma. However, the opposite seems to be true, because viral infections are often associated with the exacerbation of asthma. For this reason, we investigated what effect an influenza A (flu) virus infection has on the development of asthma. We found that flu infection 1, 3, 6, or 9 wk before allergen airway challenge resulted in a strong suppression of allergen-induced airway eosinophilia. This effect was associated with strongly reduced numbers of Th2 cells in the airways and was not observed in IFN-gamma- or IL-12 p35-deficient mice. Mice infected with flu virus and immunized with OVA showed decreased IL-5 and increased IFN-gamma, eotaxin/CC chemokine ligand (CCL)11, RANTES/CCL5, and monocyte chemoattractant protein-1/CCL2 levels in the bronchoalveolar lavage fluid, and increased airway hyperreactivity compared with OVA-immunized mice. These results suggest that the flu virus infection reduced airway eosinophilia by inducing Th1 responses, which lead to the inefficient recruitment of Th2 cells into the airways. However, OVA-specific IgE and IgG1 serum levels, blood eosinophilia, and goblet cell metaplasia in the lung were not reduced by the flu infection. Flu virus infection also directly induced AHR and goblet cell metaplasia. Taken together, our results show that flu virus infections can induce, exacerbate, and suppress features of asthmatic disease in mice.

Allergens↗
PubMed2003

MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes.

The ability to activate CD4 T cells is restricted to antigen-presenting cells that express major histocompatibility complex (MHC) class II molecules. Parenchymal cells normally do not express MHC class II molecules; however, in clinical hepatitis, viral or autoimmune, hepatocytes often exhibit aberrant MHC class II expression. It is not known whether MHC class II-expressing hepatocytes can function as antigen-presenting cells, but it has been suggested that aberrant MHC class II expression by parenchymal cells may cause autoimmune disease. Therefore, we generated transgenic mice that specifically overexpress class II transactivator molecules in hepatocytes. Hepatocytes from these mice exhibited stable MHC class II expression and were used to stimulate CD4 T cells from T-cell receptor transgenic mice and CD4 T-cell lines. MHC II-expressing hepatocytes featured costimulatory CD80 molecules and could serve as antigen-presenting cells that were able to process protein antigen and to activate specific CD4 T cells. Nevertheless, the transgenic mice with aberrant hepatocellular MHC class II expression did not exhibit any symptoms of autoimmune disease. In conclusion, MHC II-expressing hepatocytes, as found in clinical hepatitis, can present antigen and activate CD4 T cells. The ability of hepatocytes to present antigen on MHC II molecules does not seem to be a sufficient cause for inflammatory autoimmunity and hepatitis. However, we still need to explore whether such antigen presentation is occurring in vivo. The transgenic mice described in this study may serve as a model to study the immune interaction of hepatocytes and CD4 T cells in both in vitro and in vivo.

Animals↗
PubMed2003

The streptococcal exotoxin streptolysin O activates mast cells to produce tumor necrosis factor alpha by p38 mitogen-activated protein kinase- and protein kinase C-dependent pathways.

Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-alpha). Mast cell-derived TNF-alpha plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF-alpha peaked approximately 4 h after stimulation with SLO. Production of TNF-alpha was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-alpha. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-alpha. However, hyperstimulation of mast cells might also lead to overproduction of TNF-alpha, which would then promote the development of toxic streptococcal syndromes.

Animals↗
PubMed2002

Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells.

Regulatory CD4(+)CD25(+) T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact-mediated suppression of conventional CD4(+) T cells by human CD25(+) Treg cells is fixation resistant, independent from membrane-bound TGF-beta but requires activation and protein synthesis of CD25(+) Treg cells. Coactivation of CD25(+) Treg cells with Treg cell-depleted CD4(+) T cells results in anergized CD4(+) T cells that in turn inhibit the activation of conventional, freshly isolated CD4(+) T helper (Th) cells. This infectious suppressive activity, transferred from CD25(+) Treg cells via cell contact, is cell contact-independent and partially mediated by soluble transforming growth factor (TGF)-beta. The induction of suppressive properties in conventional CD4(+) Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-beta in CD25(+) Treg cell-induced immunosuppression.

CD4-Positive T-Lymphocytes↗
PubMed2002

The nasal epithelium as a factory for systemic protein delivery.

We have previously shown that recombinant Sendai virus (SeV) produces efficient in vivo airway epithelial gene transfer. The ability to produce therapeutic levels of circulating proteins following noninvasive gene transfer would have widespread clinical application. Here, we compared nose, lung, and skeletal muscle for the ability to produce circulating levels of the secreted mouse antiinflammatory cytokine interleukin-10 (IL10) following SeV-mediated gene transfer. High levels of serum IL10 were obtained from each site with a potency order of lung > nose > muscle for a given viral titer. Serum levels from each site were within the likely required range for anti-inflammatory effects. The combination of a high-efficiency gene transfer agent (SeV) and sites that can be assessed noninvasively (nose or lung) may circumvent several current challenges to gene therapy.

Animals↗
PubMed2002

Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis.

Threshold levels of individual NFAT factors appear to be critical for apoptosis induction in effector T cells. In these cells, the short isoform A of NFATc1 is induced to high levels due to the autoregulation of the NFATc1 promoter P1 by NFATs. P1 is located within a CpG island in front of exon 1, represents a DNase I hypersensitive chromatin site, and harbors several sites for binding of inducible transcription factors, including a tandemly arranged NFAT site. A second promoter, P2, before exon 2, is not controlled by NFATs and directs synthesis of the longer NFATc1/B+C isoforms. Contrary to other NFATs, NFATc1/A is unable to promote apoptosis, suggesting that NFATc1/A enhances effector functions without promoting apoptosis of effector T cells.

Alternative Splicing↗
PubMed2002

Immature, but not inactive: the tolerogenic function of immature dendritic cells.

The induction of antigen-specific T cell tolerance and its maintenance in the periphery is critical for the prevention of autoimmunity. Recent evidence shows that dendritic cells (DC) not only initiate T cell responses, but are also involved in silencing of T cell immune responses. The functional activities of DC are mainly dependent on their state of activation and differentiation, that is, terminally differentiated mature DC can efficiently induce the development of T effector cells, whereas immature DC are involved in maintenance of peripheral tolerance. The means by which immature DC maintain peripheral tolerance are not entirely clear, however, their functions include the induction of anergic T cells, T cells with regulatory properties as well as the generation of T cells that secrete immunomodulatory cytokines. This review summarizes the current knowledge about the immunoregulatory role of immature DC that might act as guardians for the induction and maintenance of T cell tolerance in the periphery.

Animals↗
PubMed2002

Mast cells and inflammation.

Mast cells have long been recognized as potent producers of a large panel of biologically highly active mediators such as biogenic amines, arachidonic acid metabolites, cytokines and chemokines, but most of their biological functions have been elusive and speculative. By taking advantage of mast cell-deficient mice, the role of mast cells in a variety of experimental settings can now be studied in detail and such approaches have dramatically altered and enlarged our knowledge about mast cell biology and function. Herein we will focus on the role of mast cells in inflammatory reactions of diverse origin, such as delayed type hypersensitivity, atopy, immune complex-mediated inflammation and innate immune responses. From the current standpoint, there is no doubt that the most outstanding and beneficial feature of mast cells is their recently discovered ability to induce a life-saving inflammatory response rapidly upon encountering microbes and microbial constituents. Nevertheless, the picture is also emerging that mast cells are deeply involved in the induction and maintenance of a variety of severe allergic and autoimmune diseases. However, a deeper understanding of their activation and immune-modulatory capacity might open a new window for the development of curative strategies.

Animals↗
PubMed2002

Classical and alternative pathways of mast cell activation.

It has long since been recognized that mast cells are critical effectors of anaphylactic reactions, and the existence of these potentially hazardous cells has solely been justified due to their beneficial role in some infections with extracellular parasites. A novel understanding of mast cells as sentinels of the immune system has been made possible by taking advantage of mast cell-deficient mice in order to study the roles of mast cells in vivo and by detailed analyses of mast cell activation in vitro. Collectively, these experiments have revealed a variety of IgE-independent stimuli, which lead to the activation of mast cells as crucial initiators of an inflammatory response. Besides their effector function, a variety of studies reviewed herein point towards important regulatory roles for mast cells, especially regarding their interaction with other cell types.

Adenosine↗
PubMedDate not supplied

Immune regulation by regulatory T cells: implications for transplantation.

The induction of antigen-specific T cell tolerance and its maintenance in the periphery are critical for the immune system to prevent autoaggressive immune responses. Our current state of knowledge about the immunoregulatory mechanisms responsible for T cell tolerance in the periphery offers new possibilities for immunomodulation to prevent transplant rejection as well as to diminish autoimmune reaction or chronic allergy. There is growing evidence that dendritic cells, besides their well-known T cell stimulatory functions, also maintain and regulate T cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of dendritic cells, and can be further influenced and modulated by immunoregulatory cytokines and drugs. The regulatory functions of dendritic cells include the induction of T cell anergy, of T cells with regulatory properties and of T cells that produce immunosuppressive cytokines such as IL-10 or TGF-beta. Additionally, distinct subsets of resident regulatory T cells generated in the thymus play a central role in maintenance of peripheral tolerance by active suppression of effector T cell populations. These CD4(+)CD25(+) regulatory T cells inhibit a variety of autoimmune and inflammatory diseases and they are also efficient in the suppression of alloantigen responses. This review summarises the current knowledge regarding the immunoregulatory role of dendritic cells and the functional activities of resident regulatory T cells as guardians for peripheral T cell tolerance.

Dendritic Cells↗