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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; tumor ; CELL ; SYSTEM ; SYSTEMS ; DEATH ; DISEASE ; DISEASES ; DISTINCT ; COMPONENTS ; MECHANISM ; IMPACT ; ANTIGEN ; ANTIGENS ; AUTOIMMUNE-DISEASE ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; CELL-DEATH ; IMMUNE-RESPONSE ; RECEPTORS ; MULTIPLE-SCLEROSIS ; CD95 ; signaling ; CYTOKINE ; DISORDERS ; MOLECULAR-MECHANISM ; TUMORIGENESIS ; FAS ; AUTOIMMUNE-DISEASES ; IMMUNE-SYSTEM ; AICD ; death receptor ; multiple sclerosis ; function ; autoimmune disease ; NECROSIS
    Abstract: Death receptors belong to the TNF (tumor necrosis factor)/NGF (nerve growth factor) receptor superfamily. Signaling via death receptors plays a distinct role, e.g. in the immune system, where it contributes to regulation of the adaptive immune response in various ways, most notably by triggering activation-induced cell death (AICD) of T cells. Thus, dysregulation of death receptor signaling, either allowing too much or too little apoptosis, can lead to autoimmune disorders and also impacts on tumorigenesis or other diseases. In this chapter we address components, molecular mechanisms and regulation of death receptor signaling with particular focus on CD95 (APO-1, Fas). We discuss the role of death receptor-mediated AICD in regulation of the adaptive immune response against foreign and self antigens in comparison to cytokine deprivation-mediated death by neglect. Finally, the contribution of dysregulated death receptor/ligand systems to autoimmune diseases such as diabetes, multiple sclerosis and Hashimoto's thyroiditis is discussed.
    Type of Publication: Journal article published
    PubMed ID: 16394652
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  • 2
    Keywords: CELLS ; proliferation ; BLOOD ; CELL ; Germany ; human ; DISEASE ; DISEASES ; GENE-EXPRESSION ; ACTIVATION ; RESPONSES ; CELL ACTIVATION ; IFN-GAMMA ; ANTIGEN ; ANTIGENS ; autoimmune diseases ; AUTOIMMUNE-DISEASE ; CONTRAST ; SELF-ANTIGENS ; T cell ; T cell activation ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; MEMORY ; STIMULATION ; GLYCOPROTEIN ; SWEDEN ; PHENOTYPE ; allogeneic ; INDIVIDUALS ; specificity ; PERIPHERAL-BLOOD ; HEALTHY ; MULTIPLE-SCLEROSIS ; rodent ; HUMAN BLOOD ; AUTOANTIGEN ; AUTOIMMUNE ENCEPHALOMYELITIS ; CD25(+) regulatory T cell ; cord blood ; myelin oligodendrocyte glycoprotein ; SELF ; SUBPOPULATION ; THYMOCYTES
    Abstract: Regulatory T cells expressing CD25 have been shown to protect rodents from organ-specific autoimmune diseases. Similar CD25(+) cells with a memory phenotype exerting suppressive function after polyclonal or allogeneic stimulation are also present in adult human blood. We demonstrate that adult human CD25(+) cells regulate the response to myelin oligodendrocyte glycoprotein (MOG), as depletion of CD25(+) cells increases response,; of PBMC and the addition of purified CD25(+) cells suppresses MOG-specific proliferation and IFN-gamma production of CD4(+)CD25(-) T cells. In contrast, cord blood CD25(+) cells do not inhibit responses to self antigens, and only a small subpopulation of cord CD25(+) cells expresses the typical phenotype of adult regulatory T cells (CD45RA(-) and GITR(+)) enabling suppression of polyclonal responses. We conclude that activation of self-reactive T cells in normal healthy individuals is prevented by the presence of self-antigen-specific CD25+ regulatory T cells and that the majority of these cells mature after birth
    Type of Publication: Journal article published
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  • 3
    Keywords: CELLS ; IN-VITRO ; proliferation ; BLOOD ; GENE ; PROTEIN ; TISSUE ; PATIENT ; RESPONSES ; CUTTING EDGE ; INFECTION ; INDUCTION ; ANTIGEN ; CONTRAST ; T-CELL ; T-CELLS ; SUPPRESSION ; FREQUENCY ; IMMUNE-RESPONSES ; SWEDEN ; PHENOTYPE ; adenocarcinoma ; IMMUNE-RESPONSE ; IMMUNITY ; NAIVE ; INFECTIONS ; GASTRIC-CANCER ; PERSISTENCE ; TRANSCRIPTION FACTOR FOXP3
    Abstract: Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4(+) CD25(high) T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4(+) CD25(low) and CD4(+) CD25(-) cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4(+) CD25(high) T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4(+) CD25(high) cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections
    Type of Publication: Journal article published
    PubMed ID: 15618192
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  • 4
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; SURVIVAL ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; DEATH ; POPULATION ; GENE ; microarray ; MONOCLONAL-ANTIBODY ; CUTTING EDGE ; MARKER ; CONTRAST ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; FLOW ; MEMORY ; antibodies ; antibody ; HUMANS ; resistance ; CD95 ligand ; CELL-DEATH ; UP-REGULATION ; RATES ; MARKERS ; MONOCLONAL-ANTIBODIES ; POPULATIONS ; INDIVIDUALS ; CHILDREN ; FLOW-CYTOMETRY ; PERIPHERAL-BLOOD ; MULTIPLE-SCLEROSIS ; HIGH-LEVEL ; CD95 ; cord blood ; INCREASE ; FOXP3 ; LEVEL ; monoclonal antibodies ; RESISTANT ; in vivo ; regulatory T cells ; peripheral blood ; regulatory T cell ; CD4(+)CD25(+) ; CD95L ; CORD ; NEWBORN
    Abstract: Most CD4(+)CD25(hi)FOXP3(+) regulatory T cells (T-regs) from adult peripheral blood express high levels of CD45RO and CD95 and are prone to CD95L-mediated apoptosis in contrast to conventional T cells (T-convs). However, a T-reg subpopulation remained consistently apoptosis resistant. Gene microarray and 6-color flow cytometry analysis including FOXP3 revealed an increase in naive T-cell markers on the CD95L-resistant T-regs compared with most T-regs. In contrast to T-regs found in adult humans, most CD4(+)CD25(+)FOXP3(+) T cells found in cord blood are naive and exhibit low CD95 expression. Furthermore, most of these newborn T-reg are not sensitive toward CD95L similar to naive T-regs from adult individuals. After short stimulation with anti-CD3/CD28 monoclonal antibodies (mAbs), cord blood T-regs strongly up-regulated CD95 and were sensitized toward CD95L. This functional change was paralleled by a rapid up-regulation of memory T-cell markers on cord blood T-regs that are frequently found on adult memory T-reg. In summary, we show a clear functional difference between naive and memory Tregs that could result in different survival rates of those 2 cell populations in vivo. This new observation could be crucial for the planning of therapeutic application of T-reg
    Type of Publication: Journal article published
    PubMed ID: 16868256
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  • 5
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; tumor ; CELL ; Germany ; VITRO ; DEATH ; PATIENT ; MECHANISM ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUSCEPTIBILITY ; CD95 ligand ; CELL-DEATH ; LYMPHOCYTES ; INDIVIDUALS ; sensitivity ; MULTIPLE-SCLEROSIS ; GUIDELINES ; CD95 ; AUTOIMMUNE ENCEPHALOMYELITIS ; PROGRAM ; COSTIMULATION ; CD95-MEDIATED APOPTOSIS ; multiple sclerosis ; function ; DEFECT ; regulatory T cells ; EXPANSION ; regulatory T cell ; healthy individuals ; auto immunity ; DIAGNOSTIC-CRITERIA
    Abstract: Impaired suppressive function of CD4(+)CD25(high) regulatory T cells (T-reg) has been reported as a novel pathogenetic mechanism in Multiple sclerosis (MS). We addressed if high apoptosis sensitivity of MS-T-reg could explain this functional T-reg defect. T-reg from treatmentnaive MS patients showed high sensitivity towards CD95Ligand-mediated apoptosis and exhibited enhanced cell death to IL-2 and TCR-signal deprivation. Since susceptibility of T-reg to cell death was similar in MS patients and healthy controls, this cannot explain the inhibitory dysfunction of T-reg associated with MS. Furthermore, as cell death is not enhanced, therapeutic expansion of MS-T-reg in vitro should be a reasonable and novel therapeutic option. (c) 2006 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17092518
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  • 6
    Keywords: RECEPTOR ; CELLS ; IN-VITRO ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; VITRO ; VIVO ; DISEASE ; ACTIVATION ; RESPONSES ; ARTHRITIS ; CUTTING EDGE ; ANTIGEN ; T cells ; T-CELLS ; treatment ; SIGNAL ; cytokines ; IMMUNE-RESPONSES ; HUMANS ; IMMUNE-RESPONSE ; CENTRAL-NERVOUS-SYSTEM ; TARGETS ; NONOBESE DIABETIC MICE ; AUTOIMMUNE ENCEPHALOMYELITIS ; COLLAGEN-INDUCED ARTHRITIS ; AUTOIMMUNITY ; CYTOKINE ; RE ; CAPACITY ; secretion ; FOXP3 ; function ; TRANSCRIPTION FACTOR FOXP3 ; ONSET ; IMMUNOLOGICAL SELF-TOLERANCE ; in vivo ; SIGNALS ; autoimmune disease ; cure ; regulatory T cells ; regulatory mechanism ; animal model ; experimental animal models ; antigen specificity ; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ; IN-VIVO EXPANSION ; INDUCED TNF RECEPTOR ; RECEPTOR TRANSGENIC MICE
    Abstract: During the past 10 years, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have been extensively studied for their function in autoimmune disease. This review summarizes the evidence for a role of Treg in suppression of innate and adaptive immune responses in experimental models of autoimmunity including arthritis, colitis, diabetes, autoimmune encephalomyelitis, lupus, gastritis, oophoritis, prostatitis, and thyroiditis. Antigen-specific activation of Treg, but antigen-independent suppressive function, emerges as a common paradigm derived from several disease models. Treg suppress conventional T cells (Tcon) by direct cell contact in vitro. However, downmodulation of dendritic cell function and secretion of inhibitory cytokines such as IL-10 and TGF-beta might underlie Treg function in vivo. The final outcome of autoimmunity vs tolerance depends on the balance between stimulatory signals (Toll-like receptor engagement, costimulation, and antigen dose) and inhibitory signals from Treg. Whereas most experimental settings analyze the capacity of Treg to prevent onset of autoimmune disease, more recent efforts indicate successful treatment of ongoing disease. Thus, Treg are on the verge of moving from experimental animal models into clinical applications in humans
    Type of Publication: Journal article published
    PubMed ID: 16838180
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  • 7
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; GENERATION ; POPULATION ; PATIENT ; MECHANISM ; MARKER ; DONOR ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; DIFFERENCE ; resistance ; NUMBER ; AGE ; SURFACE ; BETA ; PHENOTYPE ; INDIVIDUALS ; TCR ; DE-NOVO ; PREVALENCE ; PERIPHERAL-BLOOD ; DECLINE ; MULTIPLE-SCLEROSIS ; GUIDELINES ; SUBPOPULATION ; DEFICIENCY ; SUBSET ; CAPACITY ; multiple sclerosis ; USA ; function ; correlation ; DEFECT ; immunology ; DEPLETION ; regulatory T cells ; HOMEOSTASIS ; EXPANSION ; DIAGNOSTIC-CRITERIA ; DYSFUNCTION ; GLATIRAMER ACETATE
    Abstract: The suppressive function of regulatory T cells (T-reg) is impaired in multiple sclerosis (MS) patients. The mechanism underlying the Treg functional defect is unknown. T-reg mature in the thymus and the majority of cells circulating in the periphery rapidly adopt a memory phenotype. Because our own previous findings suggest that the thymic output of T cells is impaired in MS, we hypothesized that an altered T-reg generation may contribute to the suppressive deficiency. We therefore determined the role of T-reg that enter the circulation as recent thymic emigrants (RTE) and, unlike their CD45RO(+) memory counterparts, express CD31 as typical surface marker. We show that the numbers of CD31(+)-coexpressing CD4(+)CD25(+)CD45RA(+)CD45RO-FOXP3(+) T-reg (RTE-T-g) within peripheral blood decline with age and are significantly reduced in MS patients. The reduced de novo generation of RTE-T-reg is compensated by higher proportions of memory T-reg, resulting in a stable cell count of the total T-reg population. Depletion of CD31(+) cells from T-reg diminishes the suppressive capacity of donor but not patient T-reg and neutralizes the difference in inhibitory potencies between the two groups. Overall, there was a clear correlation between T-reg-mediated suppression and the prevalence of RTE-T-reg, indicating that CD31-expressing naive T-reg contribute to the functional properties of the entire T-reg population. Furthermore, patient-derived T-reg, but not healthy T-reg, exhibit a contracted TCR V beta repertoire. These observations ggest that a shift in the homeostatic composition of T-reg subsets related to a reduced thymic-dependent de novo generation of RTE-T-reg with a compensatory expansion of memory Tmg may contribute to the Treg defect associated with MS
    Type of Publication: Journal article published
    PubMed ID: 17617625
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; TISSUE ; TUMORS ; ACCUMULATION ; MICE ; TIME ; PATIENT ; LIGAND ; IFN-GAMMA ; prognosis ; DENDRITIC CELLS ; NUMBER ; LIGANDS ; CANCER-PATIENTS ; PROGNOSTIC-SIGNIFICANCE ; STRATEGIES ; IMMUNE-RESPONSE ; REJECTION ; CANCER PATIENTS ; chemokine ; ONCOLOGY ; RE ; CAPACITY ; THERAPIES ; TUMOR TISSUE ; REGULATORY T-CELLS ; LEVEL ; USA ; survival time ; cancer research ; ANTITUMOR RESPONSES ; NATURAL-KILLER-CELL ; ECTOPIC EXPRESSION ; natural killer ; NK-CELLS ; CHEMOKINE FAMILY
    Abstract: Several studies have correlated high numbers of tumor-infiltrating natural killer (NK) cells with a good prognosis for cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the tumors in IFN-gamma receptor knockout (IFN-gamma R-/-) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of lFN-gamma in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27(high) NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the tumor tissue. Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the tumor was severely impaired. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell-dependent survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors. Exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. [Cancer Res 2008;68(20):8437-45]
    Type of Publication: Journal article published
    PubMed ID: 18922917
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  • 9
    Keywords: CELLS ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; VITRO ; GENE ; INDUCTION ; SKIN ; BETA ; FLOW-CYTOMETRY ; LEUKEMIA-CELLS ; FOXP3 EXPRESSION ; CD25 EXPRESSION ; CD4(+)CD25(-) T-CELLS ; CUTANEOUS-LYMPHOMAS ; LEUKEMIA/LYMPHOMA CELLS ; PERIPHERAL-BLOOD INVOLVEMENT
    Abstract: Cutaneous T-cell lymphoma (CTCL) has been suggested by in vitro experiments to represent a malignant CD4+ T-cell proliferation with a regulatory T-cell (Treg) phenotype (CD4+CD25+FOXP3+). We investigated percentages of FOXP3+ and CD25+ cells in the blood of 15 Sezary, 14 mycosis fungoides (MF), and 10 psoriasis (Pso) patients and 20 normal healthy donors (NHDs). We found similar numbers of FOXP3+ cells in MF (10.4% of blood CD4+ cells) and Pso (11.1%) patients and NHDs (9.8%). In 8 of 15 (53%) Sezary patients, significantly reduced percentages of FOXP3+ cells were seen in blood (2.9%) and skin (10.4%). Interestingly, 6 of 15 (40%) Sezary patients showed significantly increased percentages of FOXP3+ cells (39.7% (blood), 20.3% (skin)); however, these cells did not express CD25. In these latter patients, clone-specific TCR-Vbeta-chain antibodies were used to demonstrate that these FOXP3+CD25- cells were monoclonal CTCL tumor cells. FOXP3+CD25- CTCL tumor cells showed a highly demethylated status of the foxp3 gene locus similar to Treg cells, and they were functionally able to suppress IL-2 mRNA induction in TCR-stimulated conventional T cells. Thus, FOXP3+CD25- CTCL tumor cells with functional features of Treg cells define a subgroup of Sezary patients who might carry a different prognosis and might require differential treatment.
    Type of Publication: Journal article published
    PubMed ID: 19626037
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  • 10
    Keywords: DISEASE ; FREQUENCY ; PATHOGENESIS ; MULTIPLE-SCLEROSIS ; LUPUS-ERYTHEMATOSUS ; LOCALIZED SCLERODERMA ; DEFECTIVE SUPPRESSOR FUNCTION ; BOSENTAN ; ENDOTHELIN-RECEPTOR ANTAGONIST ; PULMONARY ARTERIAL-HYPERTENSION
    Abstract: OBJECTIVE: To determine the frequency and suppressive capacity of regulatory T cells (T(reg)) and their association with clinical parameters in patients with systemic scleroderma (SSc). METHODS: Peripheral blood from 25 patients with SSc, 15 patients with localised scleroderma (LS) and 29 healthy controls (HC) was studied. Analysis of CD4(+) forkhead box P3 (Foxp3)(+) and CD4(+)CD25(++)Foxp3(+) Treg subpopulations was carried out by flow cytometry and cell proliferation was quantified by (3)H-thymidine incorporation. Quantitative analysis of T(reg) was further performed in skin biopsies from 17 patients with SSc and 21 patients with LS using anti-CD4 and anti-Foxp3 monoclonal antibodies for immunohistochemistry. RESULTS: The frequency of CD4(+)Foxp3(+) and CD4(+)CD25(++)Foxp3(+) Treg in peripheral blood from patients with SSc was not significantly different from that of patients with LS or HC. The suppressive capacity of CD4(+)CD25(++) Treg in SSc was also found to be similar to that of HC. Phenotypic and functional data revealed no significant difference between the limited or diffuse form of SSc. Moreover, therapy with bosentan showed no significant effect on the frequency of T(reg) during the course of the disease. However, the frequency of T(reg) in skin lesions from patients with SSc or LS, determined as the percentage of CD4(+) cells expressing Foxp3 in the inflammatory infiltrate, was significantly reduced compared with other inflammatory skin diseases. CONCLUSION: These results indicate that although the authors found no defect in the frequency or function of peripheral T(reg) subpopulations, the reduction of CD4(+)Foxp3(+) T(reg) in the skin of patients with SSc may be important in the pathogenesis of the disease.
    Type of Publication: Journal article published
    PubMed ID: 21097800
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