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H Schulze-Koops

Publications and source records attributed to H Schulze-Koops.

At least 19 recordsLinked to original sources
PubMed2001

Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation.

To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH(2)-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.

Adult↗
PubMed2001

The balance of Th1/Th2 cytokines in rheumatoid arthritis.

It has been suggested that rheumatoid inflammation is mediated by activated pro-inflammatory T helper type I cells. In contrast, immunomodulatory T helper type 2 cells and their cytokines, in particular interleukin-4, are rarely found. This chapter reviews the concept of the Th1/Th2 dichotomy and summarizes the functions of the signature cytokines of the T helper subsets. We discuss current knowledge of the immunopathogenesis of rheumatoid arthritis and its related animal model, collagen induced arthritis, with regard to the Th1/Th2 paradigm. The accumulating evidence for a T helper type 1 driven inflammation and the implications for future therapy are delineated.

Animals↗
PubMed2001

Treatment of rheumatoid arthritis in the third millennium.

Immense progress has been made in recent years in the management of patients with autoimmune diseases, such as rheumatoid arthritis (RA). This progress is largely owed to the advances in our understanding of cellular and molecular mechanisms involved in the pathogenesis of inflammation and autoimmunity and the substantially improved knowledge of molecular biology. In this editorial review, we delineate recent developments in the treatment of RA with a focus on biological therapeutics. we outline the concerns and open questions risen by the current studies and we portray future expectations based on the recent observations from those trials with biological treatment interventions.

Antibodies, Monoclonal↗
PubMed2000

Rheumatoid synovial CD4+ T cells exhibit a reduced capacity to differentiate into IL-4-producing T-helper-2 effector cells.

CD4+ memory T cells (Tm) from rheumatoid arthritis peripheral blood (RAPB) or peripheral blood from normal donors produced IL-2, whereas fewer cells secreted IFN-gamma or IL-4 after a brief stimulation. RAPB Tm contained significantly more IFN-gamma producers than normal cells. Many rheumatoid arthritis (RA) synovial Tm produced IFN-gamma alone (40%) and fewer cells produced IL-2 or IL-4. An in vitro model was employed to generate polarized T-helper (Th) effectors. Normal and RAPB Tm differentiated into both IFN-gamma- and IL-4-producing effectors. RA synovial fluid (RASF) Tm demonstrated defective responsiveness, exhibiting diminished differentiation of IL-4 effectors, whereas RA synovial tissue (RAST) Tm exhibited defective generation of IFN-gamma and IL-4 producers.

Adult↗
PubMed2000

Where is biological therapy going?

The substantial progress in our understanding of molecular and cellular biology has allowed us to design biological therapeutics ('biologicals') with defined targets and effector functions. These biologicals have greatly contributed to our current knowledge of pathogenetic mechanisms in autoimmune diseases. However, although some of the biologicals have been extremely successful in treating the symptoms of chronic inflammation, biological therapy has not yet met the expectations of permanently silencing the chronic immune response. In this commentary we discuss current concepts and future directions of biological therapy, and the potential usefulness of biologicals as a treatment of human autoimmune diseases in appropriate critical applications with the use of suitably designed agents.

Autoimmune Diseases↗
PubMed1999

Altered memory T cell differentiation in patients with early rheumatoid arthritis.

The chronic immune response in rheumatoid arthritis (RA) might be driven by activated Th1 cells without sufficient Th2 cell differentiation to down-modulate inflammation. To test whether disordered memory T cell differentiation contributes to the typical Th1-dominated chronic inflammation in RA we investigated differentiation of resting CD4+ memory T cells in patients with early (6 wk to 12 mo) untreated RA and in age- and sex-matched healthy controls in vitro. No difference in cytokine secretion profiles of freshly isolated memory T cells was detected between patients and controls. A cell culture system was then employed that permitted the differentiation of Th effectors from resting memory T cells by short term priming. Marked differences were found in response to priming. Th2 cells could be induced in all healthy controls by priming with anti-CD28 in the absence of TCR ligation. By contrast, priming under those conditions resulted in Th2 differentiation in only 9 of 24 RA patients. Exogenous IL-4 could overcome the apparent Th2 differentiation defect in seven patients but was without effect in the remaining eight patients. In all patients a marked decrease in IL-2-producing cells and a significant increase in well-differentiated Th1 cells that produced IFN-gamma but not IL-2 were evident after priming with anti-CD3 and anti-CD28. The data suggest that CD4+ memory T cells from patients with early untreated RA manifest an intrinsic abnormality in their ability to differentiate into specific cytokine-producing effector cells that might contribute to the characteristic Th1-dominated chronic (auto)immune inflammation in RA.

Adult↗
PubMed1999

Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose.

Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells. Although it can lead to the release of calcium ions in T lymphocytes, it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chromatography analysis, we show that stimulation of the T-cell receptor/CD3 (TCR/CD3) complex results in activation of a soluble ADP-ribosyl cyclase and a sustained increase in intracellular levels of cADPR. There is a causal relation between increased cADPR concentrations, sustained calcium signalling and activation of T cells, as shown by inhibition of TCR/CD3-stimulated calcium signalling, cell proliferation and expression of the early- and late-activation markers CD25 and HLA-DR by using cADPR antagonists. The molecular target for cADPR, the type-3 ryanodine receptor/calcium channel, is expressed in T cells. Increased cADPR significantly and specifically stimulates the apparent association of [3H]ryanodine with the type-3 ryanodine receptor, indicating a direct modulatory effect of cADPR on channel opening. Thus we show the presence, causal relation and biological significance of the major constituents of the cADPR/calcium-signalling pathway in human T cells.

Adenosine Diphosphate Ribose↗
PubMed1999

Human CD4+ T cell differentiation and effector function: implications for autoimmunity.

Human CD4+ memory T cells progress through stages of postthymic differentiation that have been characterized by distinct phenotypes. We have investigated the factors regulating cytokine production, and the correlation between phenotype and effector function in normal and autoimmune individuals. These studies suggest that antigen-induced proliferation in the periphery drives CD4+ T cells through successive stages of differentiation that culminate in optimal effector function and resistance to external modulatory influences. Moreover, these studies support the concept that in autoimmune individuals, the chronic accumulation of differentiated proinflammatory T cells perpetuate the inflammatory response resulting in aggressive disease.

Arthritis, Rheumatoid↗
PubMed1998

Human memory T cell differentiation into Th2-like effector cells is dependent on IL-4 and CD28 stimulation and inhibited by TCR ligation.

Freshly isolated memory T cells primarily produced IL-2 and small amounts of IL-4 and IFN-gamma after stimulation in vitro. Priming for 5 days in vitro with anti-CD28 monoclonal antibodies (mAb) alone markedly increased production of IL-4. In comparison to fresh cells, the increase in the amount of IL-4 secreted reflected a marked increase in the number of IL-4-producing cells. Stimulation with immobilized anti-CD3 mAb during priming limited subsequent IL-4 production. By contrast, IFN-gamma production from in vitro primed memory T cells was directly correlated to the concentration of priming anti-CD3 mAb. IL-2 production by all restimulated cells was decreased. The differentiation of IL-4-producing cells could be blocked by antibody to IL-4 and enhanced by the addition of recombinant IL-4 as well as antibody to IFN-gamma. Of note, the IL-4-producing effector cells induced from in vitro priming derived from the early CD27pos memory T cell subset, whereas the small CD27neg differentiated memory subset produced IL-4 without in vitro priming. The results indicate that memory T cells can be directed to differentiate into IL-4-producing effector cells by stimulation via CD28 and IL-4, whereas increasing engagement of the TCR limits Th2 memory cell differentiation.

Antibodies, Monoclonal↗
PubMed1998

Effects of Tripterygium wilfordii hook F extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production.

OBJECTIVE: Extracts of the Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) have been reported to be effective in the treatment of patients with a variety of inflammatory and autoimmune diseases, but the mechanism of this therapeutic effect has not been completely delineated. The present study was designed to assess the effects of TWHF on the in vitro synthesis of prostaglandin E2 (PGE2) and on the expression of the cyclooxygenase isoforms, COX-1 and COX-2, in various human cell types. METHODS: Monocytes from human peripheral blood (HM), fibroblasts from rheumatoid arthritis synovial tissue (RASF), human neonatal foreskin fibroblasts (HFF), and the histiocytic cell line U937 were cultured for designated time periods with or without lipopolysaccharide (LPS), and in the presence or absence of varying concentrations of the following inhibitors: the methanol/chloroform (T2) extract of TWHF, the ethyl acetate (EA) extract of TWHF, a purified diterpenoid component of TWHF (triptolide), dexamethasone, and indomethacin. Culture supernatants were harvested for PGE2 content assays. Total RNA was extracted from the cells and analyzed for COX-1 and COX-2 messenger RNA (mRNA) expression using reverse transcriptase-polymerase chain reaction or Northern blotting. RESULTS: Both the T2 and EA extracts inhibited PGE2 synthesis in the LPS-stimulated HM, RASF, and HFF cells, which was reflected by a marked suppression in the levels of mRNA for COX-2. In contrast, neither extract inhibited PGE2 production in U937 cells that did not express COX-2. Triptolide also inhibited LPS-stimulated induction of COX-2 mRNA and synthesis of PGE2, at the same inhibitory concentration as seen with the EA extract. The effects of T2, EA, and triptolide paralleled the inhibitory action of dexamethasone. CONCLUSION: The data indicate that both the T2 and EA extracts of TWHF, as well as the triptolide component, inhibit PGE2 production in a variety of human cells by blocking the up-regulation of COX-2.

Acetates↗
PubMed1998

Reduction of Th1 cell activity in the peripheral circulation of patients with rheumatoid arthritis after treatment with a non-depleting humanized monoclonal antibody to CD4.

OBJECTIVE: To test the hypothesis that administration of a non-depleting monoclonal antibody (Mab) to CD4 may alter T cell function in patients with rheumatoid arthritis (RA), possibly associated with clinical benefit. METHODS: The patients with RA treated were a subset from a multicenter, placebo-controlled, randomized, double-blind trial and were randomized into one of 2 treatment groups receiving placebo or +/-450 mg of a humanized anti-CD4 Mab (ORTHOCLONE OKTcdr4a) per week for 2 treatment cycles. For the third cycle, patients who had received Mab during the first 2 courses were given placebo, whereas the patients who were originally given placebo received anti-CD4 Mab. To evaluate the impact of anti-CD4 Mab treatment on T cell functions, cytokine production by mitogen-stimulated peripheral blood T cells was monitored, cytokine mRNA levels were assessed in stimulated peripheral blood mononuclear cells (PBMC) by semiquantitative polymerase chain reaction, and clinical activity was also measured during the study. RESULTS: Administration of the anti-CD4 Mab, but not placebo, was followed by an immediate transient clinical benefit accompanied by a significant decrease in C-reactive protein levels. There was no significant change in the number of circulating CD4+ T cells. However, 7 weeks after the second Mab treatment, interleukin 2 (IL-2) and IFN-gamma mRNA levels were significantly reduced in all anti-CD4 Mab treated patients, but neither was reduced in placebo-treated patients. CONCLUSION: Clinical improvement in patients with RA treated with a non-depleting Mab to CD4 may be related to a decrease in the function of IL-2 and IFN-gamma producing Th1 cells.

Antibodies, Monoclonal↗
PubMed1997

Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation.

OBJECTIVE: To determine whether monocytes in rheumatoid arthritis (RA) are activated to produce proinflammatory cytokines in the peripheral circulation before entering the synovium and whether the pattern of cytokines that is expressed correlates with disease activity. METHODS: Cytokine messenger RNA (mRNA) levels were assessed in peripheral blood mononuclear cells (PBMC) from 14 RA patients and 14 healthy controls by semiquantitative reverse transcription-polymerase chain reaction technology. The method employed was sufficiently sensitive to assess cytokine mRNA levels in freshly isolated cells without the necessity of in vitro stimulation. Thus, an estimate of the in vivo state of activation could be obtained. RESULTS: Interleukin-8 (IL-8) mRNA levels were elevated in all 14 RA patients compared with normal controls, whereas 7 of 14 RA patients had elevated levels of mRNA for IL-6 or IL-10. IL-1beta mRNA levels were below the normal range in 3 of 14 patients, within normal limits in 4 of 14, and elevated in 7 of 14. Tumor necrosis factor alpha mRNA levels were within the normal range in 9 of 14 patients and below normal in 5 of 14. There was a statistically significant difference between the mean IL-10 (P < 0.05) and IL-8 (P < 0.001) mRNA levels in RA patients and normal controls. Of note, the 7 patients with elevated IL-1beta mRNA levels also expressed the highest levels of IL-8 mRNA. Whereas a strong correlation between the expression of IL-1beta and IL-8 mRNA (P < 0.001) was found, expression of all other mRNA occurred independently of each other. Levels of cyclooxygenase 2 (COX-2) mRNA were also determined to evaluate the status of myeloid cell activation more completely. COX-2 mRNA levels were within the normal range in 4 of 11 patients and below normal in 7 of 11, but did not correlate with the expression of any of the cytokine mRNA. CONCLUSION: Elevated levels of mRNA for selected cytokines that are predominantly produced by monocytes can be found in the PBMC of many RA patients. The data indicate that myeloid precursor cells become activated to produce cytokines before they enter the synovium, a finding which emphasizes the systemic nature of RA.

Adult↗
PubMed1997

Repeat treatment of rheumatoid arthritis patients with a murine anti-intercellular adhesion molecule 1 monoclonal antibody.

OBJECTIVE: To assess the safety and efficacy of a second course of treatment with a murine monoclonal antibody (MAb) to intercellular adhesion molecule 1 (ICAM-1; CD54) in active rheumatoid arthritis (RA). METHODS: In an open-label study, 8 patients who had previously received a course of anti-ICAM-1 MAb received a second course. RESULTS: The second course of therapy was associated with adverse effects suggestive of immune complex formation. Such adverse effects were not seen during the initial course of therapy. Clinical efficacy associated with the second course of therapy was less than that observed in the first course. CONCLUSION: Repeated courses of therapy with a murine MAb to ICAM-1 would probably not be a useful therapeutic strategy in patients with RA, probably because of its immunogenicity.

Animals↗
PubMed1996

Persistent reduction in IL-6 mRNA in peripheral blood mononuclear cells of patients with rheumatoid arthritis after treatment with a monoclonal antibody to CD54 (ICAM-1).

There is persistent excessive production of a number of pro-inflammatory cytokines in patients with rheumatoid arthritis (RA). A number of experimental therapies have been found to be effective in the treatment of RA, although the effects of these therapies on cytokine production have not been evaluated. One such experimental therapy involves administration of a MoAb to intercellular adhesion molecule-1 (ICAM-1) that has been shown to be clinically beneficial in approximately 60% of the patients, with some patients responding for up to 11 months. The current studies were carried out to determine whether the success of this therapy was associated with changes in mRNA levels for pro-inflammatory and other monocyte-derived cytokines in peripheral blood mononuclear cells (PBMC). Cytokine mRNA levels were assessed in freshly isolated unstimulated PBMC by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) after minimal in vitro manipulation of the cells. Anti-ICAM-1 MoAb administration was followed by an increase in IL-1 beta, IL-8, and tumour-necrosis factor-alpha (TNF-alpha) mRNA detected at 2 or 24 h after the initial infusion in the clinical responders, but no persistent change in these cytokine mRNA levels were observed that correlated with clinical benefit. By contrast, IL-6 mRNA levels declined immediately after the first MoAb infusion and reached pretreatment values variably after the 5 day treatment course. IL-6 mRNA levels remained significantly reduced in patients responding to therapy 1 months after treatment. Fluctuations in monocyte numbers within the PBMC after treatment did not account for the observed changes in cytokine mRNA levels. The results suggest that a decline in IL-6 mRNA levels is a pharmacological action of the MoAb to ICAM-1. Moreover, persistently diminished IL-6 mRNA levels induced by anti-ICAM-1 MoAb might be associated with the long-term benefit of this therapy. In addition, monitoring the activation status of monocytes in circulating PBMC may be useful in predicting response to therapy and warrants further investigation in a larger study population.

Antibodies, Monoclonal↗