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  • 1
    Keywords: carcinoma ; ENDOTHELIAL GROWTH-FACTOR ; IN-VIVO ; MICE ; adenocarcinoma ; ANTITUMOR IMMUNITY ; inflammation ; CLINICAL-SIGNIFICANCE ; TUMOR-ASSOCIATED MACROPHAGES ; REGULATORY T-CELLS
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDAC-bearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4(+) T cells in tumors and IFN gamma level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.
    Type of Publication: Journal article published
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  • 2
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; Germany ; human ; THERAPY ; GENERATION ; SYSTEM ; DISEASE ; PATIENT ; ACTIVATION ; CUTTING EDGE ; MECHANISM ; REDUCTION ; TRANSPLANTATION ; INDUCTION ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; TOLERANCE ; FREQUENCY ; FREQUENCIES ; STAGE ; DISRUPTION ; NUMBER ; BONE-MARROW-TRANSPLANTATION ; PERIPHERAL-BLOOD ; stem cell transplantation ; inflammation ; EX-VIVO ; PHASE ; graft-versus-host disease ; INHIBIT ; regulatory T cells ; peripheral blood ; EXPANSION ; regulatory T cell ; stem cell ; STEM-CELL ; CD4(+)CD25(+) ; CELL TRANSPLANTATION ; GvHD ; CLINICAL COURSE ; allogeneic stem cell transplantation ; immunoregulation
    Abstract: The mechanisms that induce and control the alloimmune inflammation of graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (allo-SCT) are still incompletely understood. In the murine system, GvHD can be suppressed by CD4(+)CD25(+) regulatory T cells (TREG), which are generally involved in the suppression of inflammatory reactions. A disruption of the homeostasis between TREG and conventional T cells might therefore be associated with the inflammatory reactions of GvHD. We repetitively measured the frequency of TREG in the peripheral blood of 29 patients within the first 71-373 days after allo-SCT and correlated the results with the clinical course. We demonstrate that the initial phase of GvHD is associated with a significant reduction of TREG in the peripheral blood, while at later stages and during intensified immunosuppressive therapy, increased numbers of TREG appear. These results might indicate a pathogenic role for reduced numbers of TREG in the induction of human GvHD
    Type of Publication: Journal article published
    PubMed ID: 17105491
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  • 3
    Keywords: EXPRESSION ; IN-VIVO ; MODEL ; PROTEIN ; MICE ; PATIENT ; MECHANISM ; BINDING ; DELETION ; MOLECULAR-CLONING ; POLYCYTHEMIA-VERA ; chronic myeloproliferative disorders ; ELEVATED LEVELS ; C-MPL ; CONGENITAL AMEGAKARYOCYTIC THROMBOCYTOPENIA ; CYTOKINE RECEPTORS ; FACTOR RECEPTOR SUPERFAMILY ; JAK2 V617F ; THROMBOPOIETIN RECEPTOR
    Abstract: We generated mice expressing a full-length Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl(-/-) background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wildtype controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpl-transgenic Mpl(-/-) mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count. (Blood. 2009; 113: 1768-1777)
    Type of Publication: Journal article published
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  • 4
    Keywords: CELLS ; EXPRESSION ; ENZYMES ; RESPONSES ; MOUSE ; ANTITUMOR IMMUNITY ; inflammation ; HORMONES ; SEX-RELATED DIFFERENCES
    Abstract: Phosphodiesterase 5 (PDE5) is a pharmacological target in erectile dysfunction, pulmonary hypertension and in other indications. In tumor-bearing mice an inhibition of PDE5 with sildenafil prolongs survival of the animals through the augmentation of antitumor immunity, indicating the immunomodulatory properties of this drug. Effects of sildenafil on the immune system in healthy organisms are poorly investigated. In this work we showed that chronic application of sildenafil in healthy mice leads to opposite gender-dependent effects on NK cells, subpopulations of CD4(+) and CD8(+) T cells, activated conventional T cells, and to a decrease in Gr-1(+)CD11b(+) immature myeloid cells. Besides, sildenafil treatment decreases the serum concentration of interleukin-6. Ex vivo cultivation of isolated splenocytes with sildenafil results in an increase in CD4(+) T cells and a concomitant decrease in B cells and central memory CD8(+) T cells. Ex vivo modulatory properties of sildenafil are not gender-specific, indicating the importance of sildenafil's pharmacokinetics for it immunomodulatory activity in vivo. While the PDE5 expression is equal in the splenocytes from both genders, splenocytes from female mice possess higher basal level of cGMP compared to the male ones. Moreover, cultivation of splenocytes obtained from female but not male mice with sildenafil leads to an increase in cGMP concentration, making sildenafil's pharmacodynamics also responsible for gender-specific effects of the drug. Thus, this work secures conclusive evidence that the PDE5 inhibitor sildenafil possesses immunomodulatory properties and these effects are gender-specific. Immunological clinical trials are needed to prove the potential immunomodulatory effects of sildenafil in humans.
    Type of Publication: Journal article published
    PubMed ID: 23911424
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  • 5
    Abstract: Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2alpha. Low doses of interferon-2alpha led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2alpha therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-gamma and IL-10 in the serum following the interferon-2alpha therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2alpha therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2alpha and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 24608924
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  • 6
    Keywords: IN-VIVO ; ANTIGEN ; BONE-MARROW ; adenocarcinoma ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; MELANOMA PATIENTS ; CYCLOPHOSPHAMIDE ; RANDOMIZED-TRIAL ; TUMOR-IMMUNITY
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patient's poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in TGF-beta levels in the tumors, treatment with a specific inhibitor of TGF-beta receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy. (c) 2012 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 23233419
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  • 7
    Keywords: analysis ; regulatory T cells ; DEPLETION ; in vivo ; immune responses ; T cell ; T-CELLS ; T-CELL ; T cells ; RESPONSES ; human ; IN-VIVO ; VIVO ; CELL ; CELLS ; IMMUNE-RESPONSES ; IMMUNE-RESPONSE
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: RECEPTOR ; CELLS ; IN-VITRO ; BLOOD ; CELL ; Germany ; human ; VITRO ; DISEASE ; GENE-EXPRESSION ; PATIENT ; ACTIVATION ; RESPONSES ; CUTTING EDGE ; MARKER ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; BIOLOGY ; IMMUNE-RESPONSES ; MOUSE ; TRANSGENIC MICE ; EFFICIENT ; PHENOTYPE ; HEAD ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; PERIPHERAL-BLOOD ; CYTOKINE ; EFFECTOR FUNCTION ; cell proliferation ; graft-versus-host disease ; function ; TRANSCRIPTION FACTOR FOXP3 ; CANDIDATE ; regulatory T cells ; peripheral blood ; EXPANSION ; regulatory T cell ; CD4(+)CD25(+) ; SUPPRESSOR FUNCTION
    Abstract: CD4(+)CD25(+) regulatory T cells (T-REG) are engaged in the regulation of murine and human immune responses as well as graft-versus-host disease (GvHD) after allogeneic stem-cell transplantation. Despite their suppression of GvHD they do not impair graft-versus-tumor activity in the mouse, which makes T-REG especially attractive candidates for cellular immunotherapy. T-REG comprise only 5% to 10% of CD4(+) T cells in peripheral blood and are naturally anergic, which prevented their use as therapeutic suppressor cells in the context of autoimmune or alloimmune reactions so far. We therefore developed an in vitro expansion protocol for human TREG, breaking their anergy with anti-CD3/anti-CD28-coupled paramagnetic heads and a combination of interleukin (IL)-2 and IL-15. Highly purified human T-REG; can be expanded 285-fold to 1000-fold within 20 days and keep their phenotype as well as all their suppressor functions even in the context of stimulation with mature allogeneic dendritic cells. However, we demonstrate that FoxP3 is not a reliable Marker for human T-REG as it is transiently inducible in CD4(+)CD25(-) cells upon activation with cytokines or via their T cell receptor. In addition, we Successfully expanded CD4(+)CD25(+) cells from patients after allogeneic stem-cell transplantation with or without GvHD and show that different suppressor functions might be lost independently, demonstrating that human T-REG biology is likely more complicated than previously thought
    Type of Publication: Journal article published
    PubMed ID: 16699377
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  • 9
    Keywords: IMMUNOTHERAPY ; pancreatic cancer ; immunosuppression ; regulatory T cells
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of malignancy. Via a broad stimulation of the immune system, PDAC activates both antitumor immune responses and immunosuppressive mechanisms. We propose that new immunotherapeutic strategies for the management of PDAC should be designed to specifically neutralize the immunosuppressive tumor microenvironment.
    Type of Publication: Journal article published
    PubMed ID: 24327934
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  • 10
    Keywords: CANCER ; carcinoma ; folinic acid ; GEMCITABINE ; REGULATORY T-CELLS ; RANDOMIZED CONTROLLED-TRIAL ; ADJUVANT CHEMOTHERAPY ; BEARING MICE ; PHASE-III TRIAL ; SUPPRESSOR-CELLS
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms, having extremely poor prognosis with a 5-year survival rate of 〈1 % and a median survival of 6 months. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently needed to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited prolonged overall and disease-free survival compared to patients with lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However, clinical data from the chemoradioimmunotherapy with interferon-alpha (IFN) trial did not point to an improved efficiency of chemoradiation combined with IFN as compared to chemoradiotherapy alone, suggesting an important role of the immune suppression induced by PDAC and/or unspecific immune stimulation. In support of this hypothesis, we found that the PDAC patients and experimental mice had an increased number of regulatory T cells and myeloid-derived suppressor cells. These results allowed us to conclude that PDAC provokes not only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should involve not only stimulation of the immune system of PDAC patients, but also exert control over the tumour immune suppressive milieu.
    Type of Publication: Journal article published
    PubMed ID: 24129765
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