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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of infectious diseases, 01 February 2011, Vol.203(3), pp.430-5
    Description: Because natural killer (NK) cells kill tumor cells and combat infections, there is growing interest in adoptively transferring NK cells to hematopoietic stem cell recipients. Unfortunately, in humans, the activity of NK cells against Aspergillus species, the major cause of invasive fungal infection in stem cell recipients, are poorly characterized. Our results show that unstimulated and interleukin-2 prestimulated human NK cells kill Aspergillus fumigatus hyphae but do not affect resting conidia. Killing is also induced by the supernatant of prestimulated NK cells and human perforin. The high levels of interferon-γ and granulocyte macrophage colony-stimulating factor produced by prestimulated NK cells are significantly reduced by Aspergillus, indicating an immunosuppressive effect of the fungus. Whereas Aspergillus hyphae activate NK cells, resting, and germinating, conidia and conidia of ΔrodA mutants lacking the hydrophobic surface layer do not. Our results suggest that adoptively transferred human NK cells may be a potential antifungal tool in the transplantation context.
    Keywords: Aspergillus Fumigatus -- Physiology ; Hyphae -- Physiology ; Killer Cells, Natural -- Physiology ; Spores, Fungal -- Physiology
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 2
    Language: English
    In: The Journal of Infectious Diseases, 15 March 2012, Vol.205(6), pp.1026-1027
    Keywords: Biological sciences -- Biology -- Physiology -- Lymphocytes
    ISSN: 00221899
    E-ISSN: 15376613
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(11), p.e27351
    Description: In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI (unstim) ) or IL-2 (1000 U/ml, 9–14 days) activated NK cells (NK-DLI (IL-2 stim) ) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI (IL-2 stim) was a rapid, almost complete loss of CD56 (bright) CD16 (dim/−) immune regulatory and CD56 (dim) CD16 (+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69 (−) NCR (low) CD62L (+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI (IL-2 stim) with the CD56 (bright) CD16 (+/−) CD69 (+) NCR (high) CD62L (−) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI (IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI (unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI (IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Hematology ; Oncology ; Pediatrics And Child Health
    E-ISSN: 1932-6203
    Source: PLoS
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  • 4
    Language: English
    In: Nutrition, May 2018, Vol.49, pp.66-73
    Description: On the basis of the immunomodulatory actions of vitamin D (VD), we investigated the effects of high-dose VD therapy over a 3 mo period on the immune response in patients with Addison's disease (AD). This randomized, controlled, crossover trial included 13 patients with AD who received either cholecalciferol (4000 IU/d) for 3 mo followed by 3 mo placebo oil or the sequential alternative placebo followed by verum. Glucocorticoid replacement doses remained stable. The primary outcome measures were changes in 25-hydroxyvitamin D3 (25(OH)D ) levels and immune cells including T helper cells (Th; CD3 CD4 ), late-activated Th cells (CD3 CD4 HLA-DR ), regulatory T cells (CD3 CD4 CD25 CD127 ), cytotoxic T cells (Tc; CD3 CD8 ), late-activated Tc cells (CD3 CD8 HLA-DR ), and monocytes. The explorative analysis included the correlation of changes with VD-related gene polymorphisms and 21-hydroxylase antibody titers. Ten of 13 patients (77%) were VD deficient. Median 25(OH)D concentrations increased significantly to 41.5 ng/ml (median changes: 19.95 ng/ml;  = 0.0005) after 3 mo of cholecalciferol treatment. Within the T-cells, only the late-activated Th (median changes: 1.6%;  = 0.02) and late-activated Tc cells (median changes: 4.05%;  = 0.03) decreased, whereas monocytes (median changes: 1.05%;  = 0.008) increased after VD therapy. T-cell changes were associated with two polymorphisms ( and ), but no changes in the 21-hydroxylase antibody titers were observed. Three months of treatment with cholecalciferol achieved sufficient 25(OH)D levels and can regulate late-activated T-cells and monocytes in patients with AD. Explorative analysis revealed potential genetic contributions. This pilot trial provides novel insights about immunomodulation in AD.
    Keywords: Adrenal Insufficiency ; Immune Cells ; Cholecalciferol ; Therapy ; Cross-Over Trial ; 25(Oh)D3 Levels ; Genetic Profiling ; Anatomy & Physiology ; Diet & Clinical Nutrition
    ISSN: 0899-9007
    E-ISSN: 1873-1244
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(11), p.e27351
    Description: In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI(unstim)) or IL-2 (1000 U/ml, 9-14 days) activated NK cells (NK-DLI(IL-2 stim)) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI(IL-2 stim) was a rapid, almost complete loss of CD56(bright)CD16(dim/-) immune regulatory and CD56(dim)CD16(+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69(-) NCR(low)CD62L(+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI(IL-2 stim) with the CD56(bright)CD16(+/-)CD69(+)NCR(high)CD62L(-) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI(IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI(unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI(IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: Progressive Neuroblastoma, 2015, Vol.20, p.163-177
    Description: Abstract Immunotherapy has emerged as an alternative strategy to treat high-risk neuroblastoma stage IV in addition to surgery and conventional radio- and chemotherapy. Today, most therapy protocols for high-risk neuroblastoma include myeloablative chemotherapy which attempts to eradicate the disease, followed by the infusion of autologous stem cells to repopulate the bone marrow. Especially for patients suffering from a relapse after autologous hematopoietic stem cell transplantation (HSCT), but also for a few patients at the early stage of disease, the transplantation of allogeneic/haploidentical stem cells has been considered. Within the last decade, these transplantation strategies have been combined with adoptive cellular therapies using donor lymphocytes with a special focus on natural killer (NK) cells. However, experience with allogeneic HSCT for neuroblastoma with and without additional cell therapies is rare. In a clinical phase I/II trial including 4 patients diagnosed with neuroblastoma stage IV, the feasibility and efficacy of haploidentical HSCT with the adoptive therapy of highly purified IL-2-activated NK cells has been shown. It is encouraging that 2 out of the 4 patients suffering from high-risk neuroblastoma stage IV are alive and well, with no evidence of disease more than 4.7 years after haploidentical HSCT and additional immunotherapy using IL-2-stimulated donor NK cells. © 2015 S. Karger AG, Basel
    ISBN: 978-3-318-05496-5
    ISSN: 1017-5989
    E-ISSN: 1662-3886
    Source: Karger Book Series
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  • 7
    In: Transfusion, September 2016, Vol.56(9), pp.2336-2345
    Description: Byline: Sabine Huenecke, Melanie Bremm, Claudia Cappel, Ruth Esser, Andrea Quaiser, Halvard Bonig, Andrea Jarisch, Jan Soerensen, Thomas Klingebiel, Peter Bader, Ulrike Koehl BACKGROUND Excessive T-cell depletion (TCD) is a prerequisite for graft manufacturing in haploidentical stem cell (SC) transplantation by using either CD34 selection or direct TCD such as CD3/CD19 depletion. STUDY DESIGN AND METHODS To optimize graft composition we compared 1) direct or indirect TCD only, 2) a combination of CD3/CD19-depleted with CD34-selected grafts, or 3) TCD twice for depletion improvement based on our 10-year experience with 320 separations in graft manufacturing and quality control. RESULTS SC recovery was significantly higher (85%, n=187 vs. 73%, n=115; p〈0.0001), but TCD was inferior (median log depletion, -3.6 vs. -5.2) for CD3/CD19 depletion compared to CD34 selection, respectively. For end products with less than -2.5 log TCD, a second depletion step led to a successful improvement in TCD. Thawing of grafts showed a high viability and recovery of SCs, but low NK-cell yield. To optimize individualized graft engineering, a calculator was developed to estimate the results of the final graft based on the content of CD34+ and CD3+ cells in the leukapheresis product. CONCLUSION Finally, calculated splitting of the starting product followed by CD3/19 depletion together with CD34+ graft manipulation may enable the composition of optimized grafts with high CD34+-cell and minimal T-cell content. Article Note: This project was supported by the Frankfurter Stiftung fur krebskranke Kinder and Hilfe fur krebskranke Kinder Frankfurt e.V., Alfred und Angelika Gutermuth-Stiftung, and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium fur Wissenschaft und Kunst (HMWK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article at the publisher's website: CAPTION(S): Material S1. Calculator for separation planning. Prior to manipulation PBSC data were entered: volume, CD3+ T-cells/A[micro]l as well as CD34+ SCs/A[micro]l (grey field). Based on aggregate quality data, defined limits for SC recovery of 85%, lower (10th percentile) and median CD3 log depletion with -3.1 and -3.6 were fixed in the calculator to calculate how much of the product to process for CD34 selection and how much for CD3/CD19-depletion. For instance, when the calculation indicated a T-cell dose〉300x103/kg bodyweight with log depletion -3.6, the decision was to split the product and to additionally do a CD34 selection. Fig. S1. Chronology of depletion quality for CD3/CD19-depletion and CD34-selection. In all flowcytometric assays the adapted ISHAGE protocol (Koehl et al.) in single platform with 7-AAD was used. In the years 2005 and 2006, quality control of grafts was measured on an EPICS XL 4-color, followed by 5-color FC500 flowcytometer. Optimizations included the implementation of the CD3 antibody for detection (SK7 clone), fluorescence minus one (FMO) control for CD3 region, criteria of measurement duration (minimum 100 events of CD3+ cells, maximum time stop 300s) and use of CD14 staining as dump channel. We could not find any statistical difference when analyzing depletion quality in regard to the year in which the purification was performed.
    Keywords: Stem Cells – Analysis ; T Cells – Analysis ; Stem Cell Transplantation – Analysis;
    ISSN: 0041-1132
    E-ISSN: 1537-2995
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  • 8
    Language: English
    In: Bone marrow transplantation, July 2018, Vol.53(7), pp.891-894
    Keywords: Hematopoietic Stem Cell Transplantation -- Methods ; Sarcoma -- Therapy ; Transplantation Conditioning -- Methods ; Transplantation, Homologous -- Methods
    ISSN: 02683369
    E-ISSN: 1476-5365
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  • 9
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 February 2015, Vol.194(4), pp.1646-53
    Description: 5-Lipoxygenase (5-LO) is the key enzyme in leukotriene biosynthesis. Leukotrienes are mediators of the innate immune system and inflammatory processes, and they might also be involved in cancer development. MicroRNAs (miRNAs) are important translational regulators and have been shown to be involved in development, differentiation, and cancer. Unraveling the miRNA network is important for understanding the cellular regulation processes. We identified two new miRNAs, miR-19a-3p and miR-125b-5p, regulating 5-LO and confirmed direct interaction by reporter gene assays. Furthermore, we investigated the regulation of 5-LO by these two miRNAs in several cell types. Inhibition of both miRNAs by antagomirs during differentiation of the myeloid cell line Mono Mac 6 led to a significant increase in 5-LO protein expression. Stimulation of human T lymphocytes with PHA resulted in a strong downregulation of 5-LO mRNA expression and in the induction of miR-19a-3p. The inhibition of miR-19a-3p with an antagomir led to a significant increase in 5-LO mRNA expression in T lymphocytes. Taken together, our data reveal that miR-19a-3p and miR-125b-5p target 5-LO in a cell type- and stimulus-specific manner.
    Keywords: Arachidonate 5-Lipoxygenase -- Biosynthesis ; Gene Expression Regulation -- Immunology ; Micrornas -- Immunology
    ISSN: 00221767
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 10
    Language: English
    In: Pediatric Hematology and Oncology, 01 August 2013, Vol.30(5), pp.349-366
    Description: The third International Conference on Immunotherapy in Pediatric Oncology was held in Frankfurt/Main, Germany, October 1-2, 2012. Major topics of the conference included (i) cellular therapies using antigen-specific and gene-modified T cells...
    Keywords: Adcc ; Antibody-Based Immunotherapy ; Car ; Chimeric Antigen Receptor ; Cik ; Cytokine-Induced Killer Cells ; Hematopoietic Stem Cell Transplantation ; Hsct ; Immunotherapy ; Natural Killer Cells Nk ; Oncology ; Medicine
    ISSN: 0888-0018
    E-ISSN: 1521-0669
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