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Biomedical subjects

Hendrik Schulze-Koops

Publications and source records attributed to Hendrik Schulze-Koops.

At least 19 recordsLinked to original sources
PubMed2006

Early detection of Richter's transformation: stable disease with dose-reduced gemcitabine and local radiation.

BACKGROUND: The occurrence of Hodgkin's lymphoma (HL) as a second aggressive lymphoid malignancy (known as Hodgkin's disease variant of Richter's transformation) is rarely observed. Response rates, even with highly aggressive therapy such as stem cell transplantation, are limited, ranging from 4 to 43%, and the medium survival time ranges from 5 to 8 months. CASE REPORT: A 72-year-old patient with a history of chronic lymphatic leukemia (CLL) was admitted with thoracic back pain and assumed progression of the CLL. The patient showed no fever, night sweats or weight loss. A computed tomography (CT) scan confirmed the progression of axillary and cervical lymph nodes. In addition, an intraspinal infiltration at the 8th thoracic vertebra (Th8) was detected. Surprisingly, histology of an extirpated lymph node demonstrated the existence of 2 tumors in the same lymph node. Infiltrates of small lymphocytes representing the pre-existing CLL (CD5-, CD20-, CD23-positive) coexisted with Reed-Sternberg Hodgkin's cells (CD30-, CD15-positive). Chemotherapy was started, combined with palliative radiation of vertebrae Th7-Th10. 12 months after diagnosis of Richter's transformation the patient is still alive without any progression of the underlying disease. CONCLUSION: We present a unique case of a Hodgkin's disease variant of Richter's transformation and CLL in the same lymph node, which was detected early because of spinal infiltration and was subsequently stabilized with reduced-dosage gemcitabine and local radiation. Additionally, we show unique pictures of 2 tumors coexisting in the same lymph node.

Aged↗
PubMed2006

IFNGR1 single nucleotide polymorphisms in rheumatoid arthritis.

On the basis of their biological function, potential genetic candidates for susceptibility to rheumatoid arthritis can be postulated. IFNGR1, encoding the ligand-binding chain of the receptor for interferon gamma, IFNgammaR1, is one such gene because interferon gamma is involved in the pathogenesis of the disease. In the coding sequence of IFNGR1, two nucleotide positions have been described to be polymorphic in the Japanese population. We therefore investigated the association of those two IFNGR1 single nucleotide polymorphisms with rheumatoid arthritis in a case-control study in a central European population. Surprisingly, however, neither position was polymorphic in the 364 individuals examined, indicating that IFNGR1 does not contribute to susceptibility to rheumatoid arthritis, at least in Caucasians.

Adolescent↗
PubMed2006

The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells.

Since the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases. In particular, p38 MAPK has a multifaceted role in CD4 T cells that have been implicated in initiating and driving sustained inflammation in autoimmune diseases, such as rheumatoid arthritis or systemic vasculitis. Here we review recent advances in the understanding of the role of the p38 MAPK signaling cascade in CD4 T cells and the consequences that its inhibition provokes in T cell functions in vitro and in vivo. These new data suggest that p38 MAPK inhibitors may elicit several unwanted effects in human autoimmune diseases but may be useful for the treatment of allergic disorders.

Animals↗
PubMed2006

Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis.

OBJECTIVE: To examine whether single-nucleotide polymorphisms (SNPs) of the interleukin-4 receptor gene IL4R influence susceptibility to, or radiographic progression in, rheumatoid arthritis (RA). METHODS: The contribution of 2 SNPs (I50V and Q551R) in the coding region of IL4R to RA susceptibility was analyzed by allele-specific polymerase chain reaction in a case-control study of 471 RA patients and 371 healthy controls. Patients with available radiographs of the hands and feet obtained 2 years after disease onset (n = 302) were stratified retrospectively according to radiologic outcome into an erosive and a nonerosive group to evaluate the association between IL4R SNPs and disease progression. RESULTS: No differences in the genotype and allele frequencies of the I50V or Q551R SNPs were identified between the RA patients and healthy controls. In contrast, significant differences in the distribution of I50V IL4R SNP genotypes between patients with erosive and nonerosive disease were observed (chi2 = 15.68, P = 0.0004). Bone erosions at 2 years after disease onset were present in 68.1% of patients homozygous for the V50 allele compared with 37.0% of patients homozygous for the I50 allele (odds ratio 3.86, P < 0.0001). This association was independent of individual factors previously associated with severe disease, such as rheumatoid factor or the HLA-DR shared epitope. On a cellular level, the V50 allele conferred significantly reduced responsiveness to interleukin-4, providing a possible mechanism for the association of the I50V IL4R polymorphism with early erosions in RA. CONCLUSION: Our data identify the I50V IL4R SNP as a novel genetic marker in RA, showing high predictive value for early joint destruction.

Arthritis, Rheumatoid↗
PubMed2005

The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors.

The mechanisms underlying the extrathymic generation of CD25+CD4 regulatory T cells (Tregs) are largely unknown. In this study the IL-4R alpha-chain-binding cytokines, IL-4 and IL-13, were identified as inducers of CD25+ Tregs from peripheral CD25-CD4 naive T cells. IL-4-induced CD25+ Tregs phenotypically and functionally resemble naturally occurring Tregs in that they are anergic to mitogenic stimulation, inhibit the proliferation of autologous responder T cells, express high levels of the Forkhead box P3 and the surface receptors glucocorticoid-induced TNFR family-related protein and CTLA-4, and inhibit effector T cells in a contact-dependent, but cytokine-independent, manner. The IL-4-induced generation of peripheral Tregs was independent of the presence of TGF-beta or IL-10, but was dependent on Ag-specific stimulation and B7 costimulation. The significance of the IL-4Ralpha-binding cytokines in the generation of Ag-specific Tregs was emphasized in a mouse model of oral tolerance, in which neutralization of IL-4 and IL-13 in mice transgenic for the TCR specific for OVA completely inhibited the expansion of OVA-specific Tregs that can be induced in untreated mice by feeding the nominal Ag. Together, our results demonstrate that IL-4 and IL-13 play an important role in generating Forkhead box P3-expressing CD25+ Tregs extrathymically in an Ag-dependent manner and therefore provide an intriguing link between the well-established immunoregulatory capacity of Th2 cells and the powerful CD25+ Treg population. Moreover, our findings might provide the basis for the design of novel therapeutic approaches for targeted immunotherapy with Tregs to known Ags in autoimmune diseases or graft-vs-host reactions.

Animals↗
PubMed2005

The role of the T cell in autoimmune inflammation.

T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as CD25+ regulatory T (Treg) cells and Th2 cells, have been identified, and recent observations suggest that in rheumatoid arthritis the function of these regulatory T cells is severely impaired. Thus, in rheumatoid arthritis, defective regulatory mechanisms might allow the breakdown of peripheral tolerance, after which the detrimental Th1-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T cell subsets to rheumatoid inflammation.

Abatacept↗
PubMed2005

Regulatory T cells in rheumatoid arthritis.

Apart from the deletion of autoreactive T cells in the thymus, various methods exist in the peripheral immune system to control specific human immune responses to self-antigens. One of these mechanisms involves regulatory T cells, of which CD4+CD25+ T cells are a major subset. Recent evidence suggests that CD4+CD25+ T cells have a role in controlling the development of autoimmune diseases in animals and in humans. The precise delineation of the function of CD4+CD25+ T cells in autoimmune inflammation is therefore of great importance for the understanding of the pathogenesis of autoimmune diseases. Moreover, the ability to control such regulatory mechanisms might provide novel therapeutic opportunities in autoimmune disorders such as rheumatoid arthritis. Here we review existing knowledge of CD4+CD25+ T cells and discuss their role in the pathogenesis of rheumatic diseases.

Arthritis, Rheumatoid↗
PubMed2005

Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor.

OBJECTIVE: Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA). METHODS: Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA. CONCLUSION: The data indicate that TNF decreases HLA-DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA-DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells. Thus, anti-TNF treatment might lead to augmented T cell activation by myeloid cells, thereby promoting immune responses to (auto)antigens and the development of antinuclear antibodies that are frequently associated with anti-TNF therapy.

Adult↗
PubMed2005

The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells.

The role of p38 mitogen-activated protein kinase in primary human T cells is incompletely understood. We analyzed in detail the role of p38 in the regulation of effector functions and differentiation of human CD4 T cells by using a p38-specific inhibitor and a dominant-negative mutant of p38. p38 was found to mediate expression of IL-10 and the Th2 cytokines IL-4, IL-5, and IL-13 in both, primary naive and memory T cells. In contrast, inhibition of p38 activity did not affect expression of the Th1 cytokines IFN-gamma and TNF induced by TCR-stimulation, but decreased IL-12-mediated IFN-gamma expression. Cytokine expression from established Th2 effector cells was also regulated by p38, however, the role of p38 was less pronounced compared to primary CD4 T cells. p38 MAPK regulated cytokine gene expression at both, the transcriptional level by activating gene transcription and the post-transcriptional level by stabilizing cytokine mRNA. As a result of the effect of p38 on IL-4 expression, p38 activity modulated differentiation of naive precursor T cells by inducing a shift of the Th1/Th2 balance toward the immuno-modulatory Th2 direction. Together, the data suggest that p38 plays a key role in human Th2 cell immune responses.

CD4-Positive T-Lymphocytes↗
PubMed2004

Generation and regulation of human Th1-biased immune responses in vivo: a critical role for IL-4 and IL-10.

Tissue damage in many human autoimmune diseases is mediated by activated autoantigen-specific Th1 cells. Delineation of the regulatory mechanisms controlling a Th1-biased human immune reaction and its pathologic potential is, therefore, a critical step in the understanding of autoimmune diseases. In this study, we introduce a novel means to investigate human Th1-biased immune responses in vivo. Intraperitoneal injection of human mononuclear cells into immunodeficient mice generates a xenogeneic Th1-biased human immune response characterized by systemic inflammation and leukocytic infiltrates with a granuloma-like architecture in the liver, and the perigastrointestinal and perirenal fatty tissue. Th1 cell activation was dependent on the presence of APCs and could be blocked by cyclosporine. Importantly, neutralization of endogenously produced IL-4 and IL-10 markedly exaggerated the immune response, whereas exogenous IL-4 and IL-10 inhibited systemic Th1 immunity. Thus, the model described in this paper presents a useful means to analyze the regulation of human immune reactions in an in vivo situation. The results suggest that both IL-4 and IL-10 contribute to controlling the development of a human Th1-biased immune reaction.

Animals↗
PubMed2004

GATA-3 in human T cell helper type 2 development.

The delineation of the in vivo role of GATA-3 in human T cell differentiation is a critical step in the understanding of molecular mechanisms directing human immune responses. We examined T cell differentiation and T cell-mediated effector functions in individuals lacking one functional GATA-3 allele. CD4 T cells from GATA-3+/- individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased T helper cell (Th)2 frequencies in vivo and in vitro. Moreover, Th2 cell-mediated effector functions, as assessed by serum levels of Th2-dependent immunoglobulins (Igs; IgG4, IgE), were dramatically decreased, whereas the Th1-dependent IgG1 was elevated compared with GATA-3+/+ controls. Concordant with these data, silencing of GATA-3 in GATA-3+/+ CD4 T cells with small interfering RNA significantly reduced Th2 cell differentiation. Moreover, GATA-3 mRNA levels increased under Th2-inducing conditions and decreased under Th1-inducing conditions. Taken together, the data strongly suggest that GATA-3 is an important transcription factor in regulating human Th2 cell differentiation in vivo.

Adolescent↗
PubMed2004

The role of the immune response against tissue transglutaminase in the pathogenesis of coeliac disease.

The development of autoimmunity to tissue transglutaminase (TGase 2) is a striking feature of coeliac disease, an enteropathy that develops in genetically susceptible individuals upon exposure to dietary gluten. IgA anti-TGase 2 autoantibodies are present in at least 98% of coeliac patients on a gluten-containing diet and provide a valuable tool for the diagnosis of the disorder. During disease development, the formation of TGase 2-gliadin complexes through TGase 2 activity appears to be central for B-cell epitope spreading from gliadin to TGase 2. However, the potential role of an immune response against TGase 2 in the pathogenesis of coeliac disease and for the development of the intestinal lesion remains unclear. Recently, an inhibitory effect of anti-TGase 2 autoantibodies from coeliac patients on TGase 2 activity in vitro has been described. Here, we report that a cellular and humoral response against TGase 2 can be induced in TGase 2 (-/-) and wildtype mice on a C57BL/6 background by s.c. immunization with human recombinant or guinea pig TGase 2 in complete Freund's adjuvant. Immunized wildtype, but not TGase 2 (-/-) mice develop periductal lymphocytic infiltrates in lacrimal glands. Although no intestinal lesions were found, this observation lends support to the concept that the development of autoimmunity against TGase 2 is a pathological event that might ultimately lead to organ damage.

Animals↗
PubMed2002

Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation.

Leflunomide, an inhibitor of de novo pyrimidine biosynthesis, has recently been introduced as a treatment for rheumatoid arthritis in an attempt to ameliorate inflammation by inhibiting lymphocyte activation. Although the immunosuppressive ability of leflunomide has been well described in several experimental animal models, the precise effects of a limited pyrimidine supply on T cell differentiation and effector functions have not been elucidated. We investigated the impact of restricted pyrimidine biosynthesis on the activation and differentiation of CD4 T cells in vivo and in vitro. Decreased activation of memory CD4 T cells in the presence of leflunomide resulted in impaired generation and outgrowth of Th1 effectors without an alteration of Th2 cell activation. Moreover, priming of naive T cells in the presence of leflunomide promoted Th2 differentiation from uncommitted precursors in vitro and enhanced Th2 effector functions in vivo, as indicated by an increase in Ag-specific Th2 cells and in the Th2-dependent Ag-specific Ig responses (IgG1) in immunized mice. The effects of leflunomide on T cell proliferation and differentiation could be antagonized by exogenous UTP, suggesting that they were related to a profound inhibition of de novo pyrimidine biosynthesis. These results indicate that leflunomide might exert its anti-inflammatory activities in the treatment of autoimmune diseases by preventing the generation of proinflammatory Th1 effectors and promoting Th2 cell differentiation. Moreover, the results further suggest that differentiation of CD4 T cells can be regulated at the level of nucleotide biosynthesis.

Adjuvants, Immunologic↗
PubMed2002

22nd European Workshop for Rheumatology Research, Leiden, The Netherlands, 28 February-3 March 2002.

The European Workshop for Rheumatology Research met this year in Leiden, The Netherlands. The Workshop provided a platform to feast on new technologies and how they have taken research programmes forward. While there will be the inevitable delay during which mechanisms are devised for analysing the huge amount of information generated by these technologies, there is a lot already to look forward to. Highlights included genomic, reverse genomic and proteomic approaches to understanding disease pathogenesis and to identifying new therapeutic targets. Opportunities for exploring whether pharmacogenomics has a place in the clinic are now a reality, and phage display technology has been applied to in vivo arthritis models to identify human synovial microvascular 'post codes'.

Europe↗
PubMed2002

Induction of cyclooxygenase-2 and enhanced release of prostaglandin E(2) and I(2) in human endothelial cells by engagement of CD40.

OBJECTIVES: The hypothesis was tested that CD40-CD154 interaction is involved in the induction of cyclooxygenase-2 and the release of prostanoids in human endothelial cells. METHODS AND RESULTS: In a coculture model of human endothelial cells and a transfected CD154 positive cell line, engagement of CD40 on endothelial cells dramatically increased the synthesis of prostacyclin, prostaglandin E(2) and thromboxane A(2). This upregulation was mediated through an induction of cyclooxygenase-2 (Cox-2), as it was blocked by Cox-2-selective inhibitors. Western blot analysis demonstrated that Cox-2 protein was markedly increased in endothelial cells following CD40 engagement, an effect that was inhibited by pretreatment of cells with an anti-CD154 antibody. CONCLUSION: The data indicate that signaling via CD40 constitutes a major pathway in human endothelial cells for the induction of Cox-2 and release of prostanoids. The CD40-Cox-2 axis thus may represent an important pathway for initiating or maintaining an inflammatory process at the vessel wall.

Blotting, Western↗