@article{HofgaardJodalBommertetal.2012, author = {Hofgaard, Peter O. and Jodal, Henriette C. and Bommert, Kurt and Huard, Bertrand and Caers, Jo and Carlsen, Harald and Schwarzer, Rolf and Sch{\"u}nemann, Nicole and Jundt, Franziska and Lindeberg, Mona M. and Bogen, Bjarne}, title = {A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0051892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131117}, pages = {e51892}, year = {2012}, abstract = {Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10\(^4\) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM.}, language = {en} } @article{ZipfelEyrichSchlegeletal.2016, author = {Zipfel, Julian and Eyrich, Matthias and Schlegel, Paul-Gerhardt and Wiegering, Verena}, title = {Disturbed B cell and DC-Homeostasis in Pediatric cGVHD Patients-Cocultivation Experiments and Review of the Literature}, series = {Clinics in Oncology}, volume = {1}, journal = {Clinics in Oncology}, number = {1097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147914}, year = {2016}, abstract = {B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of na{\"i}ve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated.}, language = {en} } @article{DirksAndresPauletal.2023, author = {Dirks, Johannes and Andres, Oliver and Paul, Luisa and Manukjan, Georgi and Schulze, Harald and Morbach, Henner}, title = {IgD shapes the pre-immune na{\"i}ve B cell compartment in humans}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1096019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304758}, year = {2023}, abstract = {B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Na{\"i}ve B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on na{\"i}ve B cells is not known. Here we assessed the impact of IgD on na{\"i}ve B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although na{\"i}ve B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the na{\"i}ve B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative na{\"i}ve B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-β7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature na{\"i}ve B cell compartment as well as reduced frequencies of IgMlo/- B cells within the mature na{\"i}ve B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct VH segments in the IgD-negative mature na{\"i}ve B cell population. We conclude that IgD expression on human na{\"i}ve B cells is redundant for generation of na{\"i}ve B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig VH segments into the pre-immune Ig repertoire and for the survival of IgMlo/- na{\"i}ve B cells known to be enriched in poly-/autoreactive B cell clones.}, language = {en} } @article{EinseleBorghaeiOrlowskietal.2020, author = {Einsele, Hermann and Borghaei, Hossein and Orlowski, Robert Z. and Subklewe, Marion and Roboz, Gail J. and Zugmaier, Gerhard and Kufer, Peter and Iskander, Karim and Kantarjian, Hagop M.}, title = {The BiTE (Bispecific T-Cell Engager) Platform: Development and Future Potential of a Targeted Immuno-Oncology Therapy Across Tumor Types}, series = {Cancer}, volume = {126}, journal = {Cancer}, number = {14}, doi = {10.1002/cncr.32909}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215426}, pages = {3192 -- 3201}, year = {2020}, abstract = {Immuno-oncology therapies engage the immune system to treat cancer. BiTE (bispecific T-cell engager) technology is a targeted immuno-oncology platform that connects patients' own T cells to malignant cells. The modular nature of BiTE technology facilitates the generation of molecules against tumor-specific antigens, allowing off-the-shelf immuno-oncotherapy. Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms. Additional BiTE molecules in development target other hematologic malignancies (eg, multiple myeloma, acute myeloid leukemia, and B-cell non-Hodgkin lymphoma) and solid tumors (eg, prostate cancer, glioblastoma, gastric cancer, and small-cell lung cancer). BiTE molecules with an extended half-life relative to the canonical BiTE molecules are also being developed. Advances in immuno-oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments.}, language = {en} }