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C B Schmidt-Weber

Publications and source records attributed to C B Schmidt-Weber.

12 recordsLinked to original sources
PubMed2006

High-altitude climate therapy reduces local airway inflammation and modulates lymphocyte activation.

High-altitude climate therapy is a well-established therapeutic option, which improves clinical symptoms in asthma. However, little is known about the underlying immunological mechanisms. The study investigates the influence of high-altitude climate therapy on airway inflammation and cellular components of specific and unspecific immune response. Exhaled NO significantly decreased within 3 weeks of therapy in patients with allergic and intrinsic, moderate and severe asthma. Interleukin-10 (IL-10)-secreting peripheral blood mononuclear cells (PBMC) increased within 3 weeks of therapy in six of 11 patients, whereas transforming growth factor-beta(1)-secreting PBMC remained stable. Furthermore, monocyte activation, assessed by CD80 expression significantly decreased during therapy. The frequency of CRTH2-expressing T cells decreased, while regulatory T cells (T(reg)) remained stable. FOXP3 and GATA-3 mRNA expression in CD4(+) T cells did not change, while interferon-gamma and IL-13 mRNA expression decreased in eight of 10 patients. The current data demonstrate that high-altitude climate therapy reduces local airway inflammation. Furthermore, monocytes switch towards a tolerogenic phenotype under high-altitude climate therapy. The T(reg)/Th2 ratio increases; however, because of the absence of antigens/allergens, no de novo differentiation of Th2 nor T(reg) cells is observed. The high-altitude climate therapy therefore may form the immunological basis for the endogenous control of allergen-driven diseases.

Adult↗
PubMed2005

Distinct leucocyte redistribution after glucocorticoid treatment among difficult-to-treat asthmatic patients.

Difficult-to-treat asthma (DTA) represents a heterogeneous subgroup of asthma. Up to now, the lack of specific diagnosis not only complicates appropriate specification and control of asthma, but also makes targeted research difficult. The aim of this study is to categorize this heterogeneous group of DTA patients (n=27; referring to the GINA guidelines) based on the distinct leucocyte redistribution (LR) after glucocorticoid (GC) treatment. Furthermore, the effect of adjuvant therapies was investigated for its impact on LR. The frequency of CD3+, CD4+, CD8+, CD14+, CD19+ and NK cells was analysed in peripheral blood before and 3 h after systemic GC treatment, along with the markers of activation HLA-DR and CD25. Within 3 h of GC administration, a significant average decrease of 16% in CD3+CD4+ (P < or = 0.001) and a 12% increase in NK-cell frequency (P < or = 0.001) clearly distinguished two groups of patients: LR-responsive and LR-unresponsive patients. The CD3+CD8+ T-cell number and activation marker remained unchanged. Patients who received adjuvant therapy, such as methotrexate or interferon-alpha, because of poor clinical response to GC showed an LR similar to that showed by responsive patients. DTA patients comprise at least two immunologically distinct groups: patients showing an immediate decrease in CD3+CD4+ T cells and an increase in NK cells following GC administration and patients lacking an immediate change. Analysis of LR not only may allow the identification of immunologic steroid resistance, but also may be of value for immunologic determination of effective steroid doses.

Antigens, CD↗
PubMed2003

SARA and Hgs attenuate susceptibility to TGF-beta1-mediated T cell suppression.

Transforming growth factor-beta1 (TGF-beta1) is a pluripotent cytokine that controls peripheral T cell tolerance mainly in mucosal immunity. It is secreted by regulatory T cells (Tr /Th3) but also by other immununologically active cells. Smad anchor for receptor activation (SARA) and hepatic growth factor-regulated tyrosine kinase substrate (Hgs) are involved in TGF-beta1 signaling. Both molecules are known to present Smad2 and Smad3 to the TGF-beta receptor complex. The role of SARA and Hgs in TGF-beta1 susceptibility of human CD4+ T cells is unclear. We demonstrate here that TGF-beta1 up-regulates SARA mRNA expression in CD4+ T cells similar to that of Smad7. However, the increase in SARA expression was lower (6.1+/-0.3-fold vs. 25+/-4.1-fold) compared with Smad7 and delayed, with a maximum at 12 h compared with 2 h. Th1 and Th2 cell subsets expressed the same levels of SARA and Hgs. Compared with resting cells, significantly lower levels of the two molecules were found in antigen/allergen- or anti-CD3/CD28-stimulated cells. Down-regulation of SARA and Hgs mRNA in preactivated CD4+ T cells was accompanied by a twofold increase in a TGF-beta1 responsive reporter gene assay. Overexpression of SARA and Hgs in T cells yielded a dose-dependent decrease in cotransfected reporter gene expression, indicating an inhibitory function of both molecules. Thus, SARA and Hgs are regulators of TGF-beta1 susceptibility in T cells and integrate regulatory signals into the influence of TGF-beta1-mediated suppression of human T cells.

Allergens↗
PubMed2003

Histamine enhances TGF-beta1-mediated suppression of Th2 responses.

Susceptibility of T cells to TGF-beta1 produced by regulatory T cells has an important impact on the induction and maintenance of peripheral tolerance and therefore on the development of autoimmunity, cancer, and allergy. Histamine not only mediates the deleterious effects of allergic reactions, it can also modulate the Th1/Th2 cell balance. We demonstrate that histamine dose-dependently enhanced TGF-beta1-mediated suppression and TGF-beta1 responsiveness of CD4+ T cells. This effect was mediated by the histamine 2 receptor (H2R), as demonstrated by receptor-specific agonists and antagonists. Furthermore, the histamine effect on TGF-beta1 responsiveness was cAMP/PKA dependent. This pathway is activated by the H2R, which is preferentially expressed on Th2 cells. Thus a higher additive effect of histamine on TGF-beta1 responsiveness was found in Th2 cells compared with Th1 cells. In fact, findings are confirmed by analysis of cytokine regulation, since activation of the H2R/cAMP pathway promoted TGF-beta1-mediated IL-4 inhibition but was ineffective in suppressing IFN-gamma. These results demonstrate that histamine supports TGF-beta1 susceptibility of T cells. Moreover, Th2 cells are more affected by histamine-enhanced TGF-beta1 suppression, which is particularly important for the regulation of allergen-specific T cells in allergic immune responses.

Adenylyl Cyclases↗
PubMed2001

DNA arrays in allergy and immunology.

The DNA array technique allows the simultaneous analysis of multiple genes. This makes it an interesting tool for studies of gene expression in various diseases that are caused by or depend on multiple genes. DNA arrays are particularly applied to define certain immunological conditions such as allergic diseases. We summarize strategies on gene expression profiling of inflammatory disease and immunologically relevant cells using DNA array technology. Using DNA arrays, gene expression analysis of CD4+ T cells of allergy patients revealed interesting differences compared to healthy individuals, but also between different allergic conditions. This comparison demonstrated that T cells differed in their capacity to regulate peripheral tolerance, neuronal innervation, chemotaxis, neovascularization and epidermal growth. On the basis of these findings the DNA array technique appears to be especially interesting for the development of powerful diagnostic tools allowing fine specification and subtyping of allergic conditions, monitoring of therapy and of tailored therapy concepts.

CD4-Positive T-Lymphocytes↗
PubMed1999

Cytokine gene activation in synovial membrane, regional lymph nodes, and spleen during the course of rat adjuvant arthritis.

Cytokine gene activation was assessed during rat adjuvant arthritis (AA) in synovial membrane (SM), popliteal lymph node (popl-LN), and spleen, using semiquantitative, competitive RT-PCR. Changes in the popl-LN were considerably higher than in spleen or SM. In the preclinical phase (day 6), cytokine mRNA elevations occurred exclusively in the popl-LN and included IFN-gamma, IL-1beta, IL-5, IL-6, and IL-10. In the acute phase (days 13-16) all three organs became involved: (i) in the SM, significant elevations were limited to IL-1beta and IL-6, which, notably, correlated positively with the degree of arthritis; (ii) in the popl-LN, IFN-gamma, IL-1beta, IL-6, and IL-10 (but not IL-5) were still elevated, while IL-2 rose significantly; (iii) in the spleen, TNF-alpha peaked simultaneously with the arthritis score (day 16) and dramatically dropped thereafter. Upon transition into the chronic phase (day 20) the following phenomena were observed: (i) IL-1beta and IL-6 were still significantly increased in the SM; (ii) IFN-gamma, IL-1beta, IL-2, IL-6, and IL-10 were still elevated in the popl-LN; and (iii) there was a progressive rise of IL-5 mRNA in the spleen, positively correlated with the arthritis score. In conclusion, cytokines with pro- and anti-inflammatory functions overlap throughout disease, but in different organ-related patterns. Local (SM) and regional (popl-LN) IL-1beta and IL-6, elevated throughout the entire course of AA, may directly contribute to disease severity. While in AA spleen TNF-alpha appears to be a systemic marker of acute disease, spleen IL-5 may be involved in disease resolution.

Animals↗
PubMed1999

IL-4 enhances IL-10 gene expression in murine Th2 cells in the absence of TCR engagement.

Both IL-4 and IL-10 are regulatory cytokines produced by Th2 cells that can down-regulate cell-mediated immune responses. The studies reported here examine the influence of various cytokines in the regulation of T cell IL-10 production. The results indicate that IL-10 gene expression by TCR transgenic Th2 cells is significantly up-regulated by IL-4 in the absence of TCR signals. IL-4 enhances both IL-10 mRNA levels and secreted protein, and this effect is not related to enhanced mRNA stability. TCR-mediated IL-10 gene expression is inhibited by cyclosporin A, but IL-4-mediated IL-10 expression is not. IL-4 also enhances IL-13 mRNA levels, to a lesser extent than IL-10, but does not significantly effect the expression of other cytokine mRNAs. Furthermore, IL-4 does not significantly enhance IL-10 expression in Th1 cells. IL-2 also enhances effector cytokine production in the absence of TCR signals, but in a subset nonspecific manner, increasing both Th2 IL-4 mRNA and Th1 IFN-gamma mRNA. These data suggest that Th2 IL-4 production may contribute to the down-regulation of immune responses by directly enhancing Th2 IL-10 production. In addition, the data clearly demonstrate that exogenous cytokines can significantly influence effector cytokine production by effector T cells without the requirement for TCR signals.

Adjuvants, Immunologic↗
PubMed1996

Apoptotic cell death in activated monocytes following incorporation of clodronate-liposomes.

The present study was performed to elucidate whether sterically stabilized liposomes laden with clodronate, which lead to depletion of macrophages (Mphis) and amelioration of experimental autoimmune arthritis in vivo, selectively affect cells of the mphi lineage in vitro. The rates of incorporation of drug-free, fluorescent liposomes and the rates of cell death following exposure to clodronate-liposomes were assessed in human peripheral blood monocytes, as well as in polymorphonuclear leukocytes (PMNs), T cells, endothelial cells, and fibroblasts, both at rest and following activation. Gel electrophoresis of nuclear extracts and ultrastructural analyses were performed to identify the modality of cell death. Monocytes, particularly upon activation, were more efficient in incorporating sterically stabilized liposomes than all other cells except PMNs. Twenty percent of resting monocytes and up to 65% of activated monocytes died within 24 h of exposure to clodronate-liposomes, whereas the other cell types, including PMNs, remained unaffected. Activated monocytes exposed to clodronate-liposomes, but not resting or activated monocytes exposed to drug-free liposomes, showed clear signs of apoptotic cell death. In most of the assays, sterically stabilized liposomes were more efficient than conventional phosphatidylcholine-liposomes. Sterically stabilized clodronate-liposomes preferentially affect cells of the mphi lineage, particularly if activated. Selective elimination of activated Mphis by apoptosis may explain both therapeutic efficacy and safety of clodronate-liposomes in experimental models of autoimmunity.

Analgesics, Non-Narcotic↗
PubMed1996

Amelioration of rat experimental arthritides by treatment with the alkaloid sinomenine.

The effects of treatment with sinomenine, a pure alkaloid extracted from the chinese medical plant Sinomenium acutum, were investigated in rat adjuvant arthritis (AA) and antigen-induced arthritis (AIA). In AA, long-term, intraperitoneal (i.p.) treatment induced significant improvement of arthritic score, hind paw swelling, body weight and erythrocyte sedimentation rate (ESR) beginning past the clinical peak of the disease. In-acute AIA, short and middle-term treatment with sinomenine around and following induction of arthritis induced a dose-dependent decrease of both joint swelling and ESR, starting after the peak of arthritis, and a significant reduction of joint destruction on day 3. There was no rebound of the arthritic signs following suspension of treatment. Long-term treatment of chronic AIA partially ameliorated clinical parameters and significantly counteracted joint destruction. Maximal plasma concentrations of 22.5 micrograms/ml, fast wash out (half-life 4.24 +/- 0.99 h; mean +/- S.E.M.) and no evidence of accumulation of sinomenine were observed following single or repeated i.p. injection of 150 mg/kg. In vitro, sinomenine markedly inhibited proliferation of synovial fibroblasts from AIA or normal rats, both at rest and following activation with either transforming growth factor beta 2 (TGF-beta 2) or interleukin-1 beta (IL-1 beta). The effect was dose-dependent and half-maximal inhibition of proliferation occurred at 20.6 micrograms/ml, that is, within the in vivo therapeutic range of the drug. Late therapeutic effects of sinomenine in rat arthritic models despite early start of treatment may be related to its antiproliferative effects on synovial fibroblasts in addition to its previously reported anti-inflammatory properties.

Adjuvants, Immunologic↗
PubMed1995

Long-term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate-containing liposomes.

OBJECTIVE: To determine whether systemic elimination of macrophages by means of clodronate-containing liposomes counteracts inflammation and joint destruction in rats with established adjuvant arthritis (AA). METHODS: Rats with AA received a total of 2.7 mg of clodronate encapsulated in liposomes in 3 intravenous doses on days 10, 11, and 12 of arthritis. Phosphate buffered saline (PBS), PBS-laden liposomes, or free clodronate were used as negative controls. Clinical, hematologic, and histopathologic signs of AA were monitored, and depletion of macrophages by clodronate-liposomes was evaluated both in the synovial membrane (SM) and in organs of the mononuclear phagocyte system (MPS). RESULTS: Clodronate-laden liposomes led to significant, long-term amelioration of the clinical signs of AA, a reduction in the erythrocyte sedimentation rate (ESR), and counteraction of joint destruction, not only immediately after treatment, but also for 2 weeks thereafter. Free clodronate induced moderate clinical improvement and a significant decrease in the ESR, but only during the late phase of AA. Drug-free vesicles even aggravated the joint destruction. Clodronate-laden liposomes did not induce significant depletion of resident macrophages in the SM, but rather, in the paracortical region of popliteal lymph nodes, in the liver, and in the marginal zone and periarteriolar lymphatic sheaths of the spleen. CONCLUSION: Clodronate-laden liposomes induce long-term amelioration of AA, even if administered for a brief period during the florid phase of the disease. The amelioration is paralleled by the elimination of macrophages in immunocompetent areas of the spleen and draining lymph nodes, but not locally in the SM. This suggests an influence of the treatment on the immunoregulatory rather than effector, functions of macrophages.

Animals↗
PubMedDate not supplied

Integration of TCR and IL-4 signals through STAT6 and the regulation of IL-4 gene expression.

Signals generated by both antigen and cytokines binding to CD4(+) T cells synergize to promote helper T cell subset differentiation. For Th2 cell commitment neither IL-4 nor T cell receptor (TCR) stimulation are sufficient to drive differentiation. Th2 differentiation requires IL-4-receptor mediated signal transducers and activators of transcription 6 (STAT6) activation, but the possibility that IL-4 can directly enhance IL-4 production by T cells has remained unclear. In this report, IL-4 is shown to increase anti-CD3 or ionomycin induced IL-4 mRNA in differentiated murine Th2 cells. Anti-CD3 or ionomycin also enhances IL-4 induction of STAT6 activation, assayed by gel shift analysis of nuclear lysates. Surprisingly, cyclosporin A (CsA) also enhances STAT6 induction. Both ionomycin and CsA also enhance IL-4-induced transcriptional activity of a STAT6-linked promoter-reporter construct. In vitro calcineurin activity reduces STAT6 interactions with DNA, and CsA or FK506 can block this effect of calcineurin. These results indicate that IL-4 and TCR-generated calcium signals interact to maximize IL-4 gene expression and STAT6 activity. Calcineurin-mediated serine dephosphorylation of STAT6 and STAT6 serine phosphorylation may counter-regulate transcriptional activity of STAT6.

Animals↗