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  • 1
    Online Resource
    Online Resource
    Tumor Cell-Derived HLA-B-Associated Transkript 3 (BAT3) Is a Ligand for NKp30 and Activates NK Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 643-643
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 643-643
    Abstract: Natural-killer (NK)-cells are lymphocytes of the innate immune system, which directly attack tumor and virus-infected cells. They provide a link between innate and adaptive immunity through crosstalk with dendritic cells (DCs) and mediate T-cell activation. Among the activating and inhibitory receptors that regulate NK cell activity, the orphan NKp30 receptor (NCR3, CD337) plays a special role as NKp30 does not only induce target cell lysis but is also crucial for the interaction between NK cells and dendritic cells. However, so far the cellular ligands for NKp30 have remained elusive. Using a yeast two hybrid approach with the extracellular NKp30 sequence as bait we were able to isolate a putative NKp30 ligand from a tumor cDNA library. Sequence analysis revealed that the cDNA encoded for BAT3 (HLA-B-associated transcript 3) which originally had been cloned from the human major histocompatibility complex by chromosome walking and mapped to chromosome 6p21.3 within the HLA complex. BAT3 was described as a nuclear protein characterized by an N-terminal ubiquitin-like region, a polyproline stretch and a highly conserved BAG-(Bcl-2-associated athanogene) domain. Until now, the function of BAT3 in mammals is not clearly defined. With BAT3-specific antibodies and by means of laser scanner microscopy and Western Blotting we demonstrate that tumor cell lines and immature as well as mature DCs express BAT3. Upon co-cultivation with NK cells or exposure to stress signals such as heat shock, we observed that BAT3 translocates from the nucleus to the cell-surface and the protein is released from tumor cells into the extracellular environment. BAT3 binds directly and specifically to NKp30 on NK cells and triggers NK cell-mediated cytokine release and NKp30-dependent cytotoxicity. The inhibition of endogenous BAT3 using polyclonal antibodies prevents tumor rejection in vivo, demonstrating that BAT3 is necessary for the tumor rejection in a xenograft tumor model. Thus, BAT3 is the long sought cellular NKp30 ligand and exhibits a novel mechanism by which a nuclear protein activates NK cells via NKp30-engagement after its release to the cell-surface and the cell environment. The isolation of the first cellular NKp30-ligand provides the basis for a better molecular understanding of NK cell-regulation and allows the development of clinical applications targeting NKp30 for the immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.643.643
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    Prenylation Inhibitors as Potential Therapeutic Drugs in Hodgkin Lymphoma.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 2513-2513
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2513-2513
    Abstract: Although the therapy of Hodgkin lymphoma has improved, patients still suffer from late toxicities and insufficient treatment of relapses. Hence, new treatment strategies are needed. Statins are used to treat hypercholesterolaemia and prevent cardiovascular disease. There is evidence for a preventive effect of statins in cancer, including lymphoma. So far, nothing is known about a therapeutic activity of statins or related drugs in Hodgkin lymphoma. Statins block the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to downstream isoprenoid products like farnesyl and geranylgeranyl-pyrophosphate, inhibiting protein prenylation and leading to apoptosis in several malignancies. The anti-tumour activity of the statin simvastatin and three specific prenylation inhibitors (FTI-277, GGTI-298 and tipifarnib) in Hodgkin lymphoma cells was evaluated in cytotoxicity and apoptosis assays. Furthermore, simvastatin was tested in a xenograft model for human Hodgkin lymphoma. First simvastatin induced caspase-related apoptosis in Hodgkin lymphoma cells via the isoprenoid pathway. The IC50 of simvastatin in cytotoxicity assays was 〈 2 μM. Second simvastatin showed high activity in a mouse model for Hodgkin lymphoma, delaying tumour establishment and inhibiting tumour growth. Finally the geranylgeranyltransferase inhibitor GGTI-298 and the farnesyltransferase inhibitors FTI-277 and tipifarnib displayed anti-tumour activity in Hodgkin lymphoma cells (approximate IC50 in cytotoxicity assays: 20, 7.5 and 〈 0.1 μM respectively). Importantly, the concentration of simvastatin that induced apoptosis in Hodgkin lymphoma cells was in the range of 2 μM. This corresponds to plasma levels reached in humans in clinical trials with high dose statins in cancer. Thus, our results suggest two possible applications of simvastatin in Hodgkin lymphoma: First simvastatin in high doses could be included in polychemotherapy regimens to improve the remission rate of relapsed patients. Second simvastatin in the cholesterol-lowering dose should be evaluated as a preventive drug for patients in remission to avoid relapses. Moreover, in comparison to other haematological malignancies, the farnesyltransferase-inhibitor tipifarnib was highly cytotoxic in Hodgkin lymphoma cells. Given its activity in clinical trials in haematological neoplasia, its clinical evaluation in Hodgkin lymphoma is warranted. Taken together, prenylation inhibitors are promising drugs for the treatment of Hodgkin lymphoma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2513.2513
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Heat Shock Protein 90 Inhibitor BIIB021 (CNF2024) Depletes NF-κB and Sensitizes Hodgkin's Lymphoma Cells for Natural Killer Cell–Mediated Cytotoxicity
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 16 ( 2009-08-15), p. 5108-5116
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 16 ( 2009-08-15), p. 5108-5116
    Abstract: Purpose: In Hodgkin's lymphoma, constitutive activation of NF-κB promotes tumor cell survival and proliferation. The molecular chaperone heat shock protein 90 (HSP90) has immune regulatory activity and supports the activation of NF-κB in Hodgkin's lymphoma cells. Experimental Design: We analyzed the effect of HSP90 inhibition on viability and NF-κB activity in Hodgkin's lymphoma cells and the consequences for their recognition and killing through natural killer (NK) cells. Results: The novel orally administrable HSP90 inhibitor BIIB021 (CNF2024) inhibited Hodgkin's lymphoma cell viability at low nanomolar concentrations in synergy with doxorubicin and gemcitabine. Annexin V/7-aminoactinomycin D binding assay revealed that BIIB021 selectively induced cell death in Hodgkin's lymphoma cells but not in lymphocytes from healthy individuals. We observed that BIIB021 inhibited the constitutive activity of NF-κB and this was independent of IκB mutations. Furthermore, we analyzed the effect of HSP90 inhibition on NK cell–mediated cytotoxicity. BIIB021 induced the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell–mediated killing. In a xenograft model of Hodgkin's lymphoma, HSP90 inhibition significantly delayed tumor growth. Conclusions: HSP90 inhibition has direct antitumor activity in Hodgkin's lymphoma in vitro and in vivo. Moreover, HSP90 inhibition may sensitize Hodgkin's lymphoma cells for NK cell–mediated killing via up-regulation of ligands engaging activating NK cell receptors. (Clin Cancer Res 2009;15(16):5108–16)
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-0213
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Human Leukocyte Antigen-B-Associated Transcript 3 Is Released from Tumor Cells and Engages the NKp30 Receptor on Natural Killer Cells
    Elsevier BV ; 2007
    In:  Immunity Vol. 27, No. 6 ( 2007-12), p. 965-974
    Details
    In: Immunity, Elsevier BV, Vol. 27, No. 6 ( 2007-12), p. 965-974
    Type of Medium: Online Resource
    ISSN: 1074-7613
    URL: Article
    DOI: 10.1016/j.immuni.2007.10.010
    RVK:
    XA 48754.8
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 2001966-X
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  • 5
    Online Resource
    Online Resource
    CD30 on extracellular vesicles from malignant Hodgkin cells supports damaging of CD30 ligand-expressing bystander cells with Brentuximab-Vedotin, in vitro
    Impact Journals, LLC ; 2016
    In:  Oncotarget Vol. 7, No. 21 ( 2016-05-24), p. 30523-30535
    Details
    In: Oncotarget, Impact Journals, LLC, Vol. 7, No. 21 ( 2016-05-24), p. 30523-30535
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    URL: Article
    DOI: 10.18632/oncotarget.v7i21
    DOI: 10.18632/oncotarget.8864
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2560162-3
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  • 6
    Online Resource
    Online Resource
    ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted Immunotherapy In vitro
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 1 ( 2007-01-01), p. 332-338
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 1 ( 2007-01-01), p. 332-338
    Abstract: CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)–expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10−/− mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies. [Cancer Res 2007;67(1):332–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-2470
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    Depletion of Cellular Cholesterol and Lipid Rafts Increases Shedding of CD30
    The American Association of Immunologists ; 2004
    In:  The Journal of Immunology Vol. 172, No. 7 ( 2004-04-01), p. 4324-4331
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 172, No. 7 ( 2004-04-01), p. 4324-4331
    Abstract: CD30, a lymphoid activation marker, is shed into the cell environment after endoproteolytic cleavage of its ectodomain. Soluble (s)CD30 is able to suppress the Th1-type immune response. Because high serum levels of sCD30 and cholesterol-lowering drugs seem to be beneficial in some Th1-type autoimmune diseases, we focused on a link between CD30 shedding and the amount of cellular cholesterol. Cholesterol depletion of human Hodgkin lymphoma- and non-Hodgkin lymphoma-derived cell lines by methyl-β-cyclodextrin led to a down-regulation of membrane-bound CD30 and increased release of sCD30. Additionally, the cholesterol-interfering drugs lovastatin, cholesterol oxidase, and filipin increased CD30 shedding. Both the down-regulation of membrane-anchored CD30 and the release of sCD30 were dependent on metalloproteinases. Using specific inhibitors, we detected TNF-α converting enzyme (TACE) as the leading enzyme responsible for cholesterol-dependent CD30 shedding. A Triton X-100-based method for lipid raft isolation revealed that CD30 was partially present in lipid rafts, whereas TACE was localized in the nonraft fractions. Disintegration of lipid rafts by cholesterol depletion might therefore lead to dynamic interactions of CD30 with TACE, resulting in enhanced shedding of CD30. Our results suggest a possible role of cholesterol-dependent shedding of CD30 in the pathogenesis of immune diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.172.7.4324
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2004
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    Anti-EGFR Antibody Cetuximab in Refractory or Relapsed Multiple Myeloma: Preliminary Results and Evaluation of Response Prediction in a Phase II Clinical Trial
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3686-3686
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3686-3686
    Abstract: INTRODUCTION: Cetuximab (Erbitux©) is an anti-epidermal growth factor receptor (EGFR) antibody approved for the treatment of colorectal cancer and head and neck cancer. EGFR is also expressed on multiple myeloma (MM) plasma and bone marrow stromal cells (BMSC). Recently, the inhibition of EGFR by small molecule inhibitors has been shown to induce apoptosis in primary myeloma cells revealing a synergistic effect with dexamethasone. Therefore, the anti-EGFR antibody cetuximab might be of clinical benefit in the treatment of MM, especially in combination with dexamethasone. Here we show preliminary data of the first clinical trial with an anti-EGFR antibody in MM and discuss possible response predictors. METHODS: Cetuximab in a loading dose of 400 mg/m2 followed by 250 mg/m2 once weekly was administered to patients with refractory or relapsed MM who had previously received at least one line of prior treatment and were not eligible to undergo autologous stem cell transplantation. Responses were assessed according to the EBMT criteria. Dexamethasone 20 mg on day 1–3 of each cycle was added starting week 5 in case of tumor progression or week 9 if no partial response (PR) or complete response (CR) was achieved with cetuximab alone. Planned treatment duration was 16 weeks (primary endpoint). Patients achieving a response or stable disease after 16 weeks of treatment could continue study medication for up to 24 further weeks. In addition, patients who had responded could start treatment according to study protocol for a second time. To assess possible predictive markers for a response to cetuximab we collected patient plasma cells to perform toxicity assays and we analyzed BMSCs of patients for IL-6 secretion after treatment with cetuximab in vitro. RESULTS: Thirteen patients have been enrolled so far. Seven patients were treated for a minimum of 16 weeks and 5 of those patients received cetuximab for at least 28 weeks. One patient still continues cetuximab treatment as single agent for more than one year. Thrombocytopenia and hyponatremia were the most common CTC grade 3 or 4 side effects with grade 3 thrombocytopenia in one patient, grade 4 thrombocytopenia in 2 patients and grade 3 hyponatremia in 3 patients. Acneiform rash CTC grade 1 occurred in all patients and 1 patient suffered from acneiform rash CTC grade 2. Two serious adverse events (SAEs) with a possible relationship to the study medication were observed: Fever and shivering requiring hospitalization in 1 patient and dyspnea in 1 patient who suffered from chronic obstructive pulmonary disease, this patient was excluded from the study after the first application of cetuximab. Three SAEs with causal relationship not likely to study drug administration were noted: Septic shock resulting in death in 1 patient, fever due to infection requiring hospitalization in 1 patient and transient atrial fibrillation in 1 patient. After 16 weeks (primary endpoint) cetuximab in combination with dexamethasone induced 3 responses (2 minimal responses (MR) and 1 partial response (PR)) and led to stable disease (SD) in 3 patients, cetuximab as single agent led to SD in 1 patient. Five of the 13 patients included did not receive the planned 16 weeks of treatment due to progressive disease (PD). Six patients were treated more than 16 weeks: 1 patient still receives cetuximab as single agent and is SD since a year and 5 patients continued treatment with cetuximab and dexamethasone in combination. There was 1 PD after 21 weeks and 2 SDs and 2 MRs after 28 weeks in this cohort. In viability assays with patient plasma cells we could demonstrate that cetuximab is cytotoxic in some of the patient samples. Furthermore, cetuximab suppressed the production of growth stimulating IL-6 in BMSCs of the patient who still receives cetuximab and remains SD. To assess whether cytotoxicity of cetuximab in patient plasma cells in vitro or cetuximab-induced inhibition of IL-6 secretion might predict response to treatment, more samples will be evaluated. CONCLUSIONS: Cetuximab is safe and effective in MM patients. Because of its favourable side effect profile it should be evaluated in clinical trials in combination with other compounds. Analyzing the effects of cetuximab on patient plasma and BMSCs might become useful for response prediction of cetuximab in MM patients in the future.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3686.3686
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    Impact of local human microbiota on the allergic diseases: Organ–organ interaction
    Wiley ; 2023
    In:  Pediatric Allergy and Immunology Vol. 34, No. 6 ( 2023-06)
    Details
    In: Pediatric Allergy and Immunology, Wiley, Vol. 34, No. 6 ( 2023-06)
    Abstract: The homogeneous impact of local dysbiosis on the development of allergic diseases in the same organ has been thoroughly studied. However, much less is known about the heterogeneous influence of dysbiosis within one organ on allergic diseases in other organs. A comprehensive analysis of the current scientific literature revealed that most of the relevant publications focus on only three organs: gut, airways, and skin. Moreover, the interactions appear to be mainly unidirectional, that is, dysbiotic conditions of the gut being associated with allergic diseases of the airways and the skin. Similar to homogeneous interactions, early life appears to be not only a crucial period for the formation of the microbiota in one organ but also for the later development of allergic diseases in other organs. In particular, we were able to identify a number of specific bacterial and fungal species/genera in the intestine that were repeatedly associated in the literature with either increased or decreased allergic diseases of the skin, like atopic dermatitis, or the airways, like allergic rhinitis and asthma. The reported studies indicate that in addition to the composition of the microbiome, also the relative abundance of certain microbial species and the overall diversity are associated with allergic diseases of the corresponding organs. As anticipated for human association studies, the underlying mechanisms of the organ–organ crosstalk could not be clearly resolved yet. Thus, further work, in particular experimental animal studies are required to elucidate the mechanisms linking dysbiotic conditions of one organ to allergic diseases in other organs.
    Type of Medium: Online Resource
    ISSN: 0905-6157 , 1399-3038
    URL: Issue
    URL: Article
    DOI: 10.1111/pai.v34.6
    DOI: 10.1111/pai.13976
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2008584-9
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  • 10
    Online Resource
    Online Resource
    Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma
    Wiley ; 2013
    In:  American Journal of Hematology Vol. 88, No. 2 ( 2013-02), p. 113-115
    Details
    In: American Journal of Hematology, Wiley, Vol. 88, No. 2 ( 2013-02), p. 113-115
    Type of Medium: Online Resource
    ISSN: 0361-8609
    URL: Article
    DOI: 10.1002/ajh.23361
    Language: English
    Publisher: Wiley
    Publication Date: 2013
    detail.hit.zdb_id: 1492749-4
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