The Experts below are selected from a list of 18396 Experts worldwide ranked by ideXlab platform
Martin Lipp - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy of b cell non hodgkin lymphoma by targeting the Chemokine Receptor CXCR5 in a preclinical mouse model
International Journal of Cancer, 2014Co-Authors: Hossein Panjideh, Gerd Muller, Mathias Koch, Frank Wilde, Susanne Scheu, Gerhard Moldenhauer, Martin LippAbstract:Bispecific antibodies are promising agents for immunotherapy. Here, we describe a quadroma-based trifunctional bispecific antibody binding the Chemokine Receptor CXCR5 and the T-cell antigen CD3 that efficiently prevents tumor growth in a mouse B-cell lymphoma model. CXCR5 regulates the tissue homeostasis of mature B cells and is highly expressed on B-cell non-Hodgkin and lymphocyte-predominant Hodgkin lymphoma, as well as on a subset of CD4(+) T cells known as follicular T-helper cells. In vitro, the bispecific CXCR5::CD3 antibody efficiently recruited effector T cells to CXCR5 expressing B cells and induced a co-stimulation-independent activation of CD8(+) and CD4(+) T cells as demonstrated by the de novo expression of CD25 and CD69, and secretion of the cytokines IFN-γ, TNF-α, IL-6 and IL-10 by peripheral blood mononuclear cells. Notably, at low antibody concentrations, CXCR5::CD3 displayed a significantly higher cytotoxic activity against autologous B cells than its parental antibodies or rituximab. In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival. Taken together, our results identify CXCR5 as a promising target for antibody-based therapies in the treatment of B-cell malignancies.
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the Chemokine Receptor CXCR5 is pivotal for ectopic mucosa associated lymphoid tissue neogenesis in chronic helicobacter pylori induced inflammation
Journal of Molecular Medicine, 2010Co-Authors: Susann Winter, Martin Lipp, Christoph Loddenkemper, Anton Aebischer, Katrin Rabel, Kirstin Hoffmann, Thomas F Meyer, Uta E HopkenAbstract:Ectopic lymphoid follicles are a key feature of chronic inflammatory autoimmune and infectious diseases, such as rheumatoid arthritis, Sjogren's syndrome, and Helicobacter pylori-induced gastritis. Homeostatic Chemokines are considered to be involved in the formation of such tertiary lymphoid tissue. High expression of CXCL13 and its Receptor, CXCR5, has been associated with the formation of ectopic lymphoid follicles in chronic infectious diseases. Here, we defined the role of CXCR5 in the development of mucosal tertiary lymphoid tissue and gastric inflammation in a mouse model of chronic H. pylori infection. CXCR5-deficient mice failed to develop organized gastric lymphoid follicles despite similar bacterial colonization density as infected wild-type mice. CXCR5 deficiency altered Th17 responses but not Th1-type cellular immune responses to H. pylori infection. Furthermore, CXCR5-deficient mice exhibited lower H. pylori-specific serum IgG and IgA levels and an overall decrease in chronic gastric immune responses. In conclusion, the development of mucosal tertiary ectopic follicles during chronic H. pylori infection is strongly dependent on the CXCL13/CXCR5 signaling axis, and lack of de novo lymphoid tissue formation attenuates chronic immune responses.
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the germinal center response is impaired in the absence of t cell expressed CXCR5
European Journal of Immunology, 2007Co-Authors: Martin Lipp, Carrie N Arnold, Daniel J Campbell, Eugene C ButcherAbstract:Germinal centers support the differentiation of memory B cells and long-lived antibody-secreting cells during infection or upon vaccination. Here, we constructed mice with T cells that selectively lack the Chemokine Receptor CXCR5 to determine if expression of this Receptor by T cells is mandatory for germinal center formation and function. In these animals, germinal centers that are properly localized in B cell follicles and contain T cells do form after immunization with a thymus-dependent antigen. However, fewer and smaller germinal centers form, resulting in a significant reduction in the frequency of germinal center B cells. The defect in germinal center formation is paralleled by decreased frequencies of isotype-switched antibody-secreting cells in the spleen and bone marrow and reduced serum concentrations of total and high-affinity hapten-specific IgG(1). The results demonstrate that although CXCR5-dependent T cell positioning is important for maximal induction and expansion of germinal centers, stimulation of isotype class switching, and development of antibody-secreting cells that seed the spleen and bone marrow, it is not absolutely required for the formation and function of follicular germinal centers.
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follicular b helper t cell activity is confined to CXCR5 hi icos hi cd4 t cells and is independent of cd57 expression
European Journal of Immunology, 2006Co-Authors: Ataur Rasheed, Martin Lipp, Hanspeter Rahn, Federica Sallusto, Gerd MullerAbstract:The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (TFH) cells are characterized by high expression of the homeostatic Chemokine Receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5hiICOShi CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting Chemokine CXCL13. CXCR5hiICOShi CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that TFH cells are only distantly related to CXCR5– and CXCR5+ central memory T (TCM) as well as effector memory T (TEM) cells present in the periphery. CXCR5hiICOShi CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636334
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follicular b helper t cell activity is confined to CXCR5 hi icos hi cd4 t cells and is independent of cd57 expression
European Journal of Immunology, 2006Co-Authors: Ataur Rasheed, Martin Lipp, Hanspeter Rahn, Federica Sallusto, Gerd MullerAbstract:The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (T(FH)) cells are characterized by high expression of the homeostatic Chemokine Receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5(hi)ICOS(hi) CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting Chemokine CXCL13. CXCR5(hi)ICOS(hi) CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that T(FH) cells are only distantly related to CXCR5(-) and CXCR5(+) central memory T (T(CM)) as well as effector memory T (T(EM)) cells present in the periphery. CXCR5(hi)ICOS(hi) CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations.
Michael Brand - One of the best experts on this subject based on the ideXlab platform.
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the Chemokine Receptor CXCR5 regulates the regenerative neurogenesis response in the adult zebrafish brain
Neural Development, 2012Co-Authors: Caghan Kizil, Stefanie Dudczig, Nikos Kyritsis, Anja Machate, Juliane Blaesche, Volker Kroehne, Michael BrandAbstract:Background Unlike mammals, zebrafish exhibits extensive neural regeneration after injury in adult stages of its lifetime due to the neurogenic activity of the radial glial cells. However, the genes involved in the regenerative neurogenesis response of the zebrafish brain are largely unknown. Thus, understanding the underlying principles of this regeneration capacity of the zebrafish brain is an interesting research realm that may offer vast clinical ramifications.
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the Chemokine Receptor CXCR5 regulates the regenerative neurogenesis response in the adult zebrafish brain
Neural Development, 2012Co-Authors: Caghan Kizil, Stefanie Dudczig, Nikos Kyritsis, Anja Machate, Juliane Blaesche, Volker Kroehne, Michael BrandAbstract:Unlike mammals, zebrafish exhibits extensive neural regeneration after injury in adult stages of its lifetime due to the neurogenic activity of the radial glial cells. However, the genes involved in the regenerative neurogenesis response of the zebrafish brain are largely unknown. Thus, understanding the underlying principles of this regeneration capacity of the zebrafish brain is an interesting research realm that may offer vast clinical ramifications. In this paper, we characterized the expression pattern of CXCR5 and analyzed the function of this gene during adult neurogenesis and regeneration of the zebrafish telencephalon. We found that CXCR5 was upregulated transiently in the RGCs and neurons, and the expression in the immune cells such as leukocytes was negligible during both adult neurogenesis and regeneration. We observed that the transgenic misexpression of CXCR5 in the ventricular cells using dominant negative and full-length variants of the gene resulted in altered proliferation and neurogenesis response of the RGCs. When we knocked down CXCR5 using antisense morpholinos and cerebroventricular microinjection, we observed outcomes similar to the overexpression of the dominant negative CXCR5 variant. Thus, based on our results, we propose that CXCR5 imposes a proliferative permissiveness to the radial glial cells and is required for differentiation of the RGCs to neurons, highlighting novel roles of CXCR5 in the nervous system of vertebrates. We therefore suggest that CXCR5 is an important cue for ventricular cell proliferation and regenerative neurogenesis in the adult zebrafish telencephalon. Further studies on the role of CXCR5 in mediating neuronal replenishment have the potential to produce clinical ramifications in efforts for regenerative therapeutic applications for human neurological disorders or acute injuries.
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injury induced brain regeneration of the adult zebrafish and the role of the Chemokine Receptor CXCR5
2012Co-Authors: Caghan Kizil, Stefanie Dudczig, Nikos Kyritsis, Anja Machate, Juliane Blaesche, Volker Kroehne, Michael BrandAbstract:Kizil et al., 2012) Background: Unlike mammals, zebrafish exhibits extensive neural regeneration after injury in adult stages of its lifetime due to the neurogenic activity of the radial glial cells. However, the genes involved in the regenerative neurogenesis response of the zebrafish brain are largely unknown. Thus, understanding the principles of this regeneration capacity of the zebrafish brain is an interesting research realm that may offer vast clinical ramifications. Results: In this paper, we characterized the expression pattern of CXCR5 and analyzed the function of this gene during adult neurogenesis and regeneration of the zebrafish telencephalon. We found that CXCR5 was upregulated transiently in the RGCs and neurons, and the expression in the immune cells such as leukocytes was negligible during both adult neurogenesis and regeneration. We observed that the transgenic misexpression of CXCR5 in the ventricular cells using dominant negative and full-length variants of the gene resulted in altered proliferation and neurogenesis response of the RGCs. When we knocked down CXCR5 using antisense morpholinos and cerebroventricular microinjection, we observed outcomes similar to the overexpression of the dominant negative CXCR5 variant. Conclusions: Thus, based on our results, we propose that CXCR5 imposes a proliferative permissiveness to the radial glial cells and is required for differentiation of the RGCs to neurons, highlighting novel roles of CXCR5 in the nervous system of vertebrates. We therefore suggest that CXCR5 is an important cue for ventricular cell proliferation and regenerative neurogenesis in the adult zebrafish telencephalon. Further studies on the role of CXCR5 in mediating neuronal replenishment have the potential to produce clinical ramifications in efforts for regenerative therapeutic applications for human neurological disorders or acute injuries.
Reinhold Forster - One of the best experts on this subject based on the ideXlab platform.
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t cell specific CXCR5 deficiency prevents rheumatoid arthritis
Scientific Reports, 2017Co-Authors: Georgios Leandros Moschovakis, Michaela Friedrichsen, Anja Bubke, Christine S Falk, Regina Feederle, Reinhold ForsterAbstract:The Chemokine Receptor CXCR5 is primarily expressed on B cells and Tfh cells and facilitates their migration towards B cell follicles. In the present study we investigated the role of the CXCL13/CXCR5 axis in the pathogenesis of rheumatoid arthritis (RA) and specifically addressed the impact of CXCR5-mediated T and B cell migration in this disease. Employing collagen-induced arthritis (CIA) we identify CXCR5 as an absolutely essential factor for the induction of inflammatory autoimmune arthritis. CXCR5-deficient mice and mice selectively lacking CXCR5 on T cells were completely resistant to CIA, showed impaired germinal center responses and failed to mount an IgG1 antibody response to collagen II. Selective ablation of CXCR5 expression in B cells also led to suppression of CIA owing to diminished GC responses in secondary lymphoid organs (SLO) and impaired anti-collagen II antibody production. Chimeric mice harboring CXCR5-proficient and CXCR5-deficient immune cells revealed SLO and not the synovial tissue as the compartment where CXCR5-mediated cell migration induces autoimmune inflammation in arthritis. Thus our data demonstrate that CXCR5-mediated co-localization of Tfh cells and B cells in SLOs is absolutely essential for the induction of RA and identify CXCR5 and Tfh cells as promising therapeutic targets for the treatment of RA.
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t cell specific CXCR5 deficiency prevents rheumatoid arthritis
Scientific Reports, 2017Co-Authors: Georgios Leandros Moschovakis, Michaela Friedrichsen, Anja Bubke, Christine S Falk, Regina Feederle, Reinhold ForsterAbstract:The Chemokine Receptor CXCR5 is primarily expressed on B cells and Tfh cells and facilitates their migration towards B cell follicles. In the present study we investigated the role of the CXCL13/CXCR5 axis in the pathogenesis of rheumatoid arthritis (RA) and specifically addressed the impact of CXCR5-mediated T and B cell migration in this disease. Employing collagen-induced arthritis (CIA) we identify CXCR5 as an absolutely essential factor for the induction of inflammatory autoimmune arthritis. CXCR5-deficient mice and mice selectively lacking CXCR5 on T cells were completely resistant to CIA, showed impaired germinal center responses and failed to mount an IgG1 antibody response to collagen II. Selective ablation of CXCR5 expression in B cells also led to suppression of CIA owing to diminished GC responses in secondary lymphoid organs (SLO) and impaired anti-collagen II antibody production. Chimeric mice harboring CXCR5-proficient and CXCR5-deficient immune cells revealed SLO and not the synovial tissue as the compartment where CXCR5-mediated cell migration induces autoimmune inflammation in arthritis. Thus our data demonstrate that CXCR5-mediated co-localization of Tfh cells and B cells in SLOs is absolutely essential for the induction of RA and identify CXCR5 and Tfh cells as promising therapeutic targets for the treatment of RA.
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The Journal of Experimental Medicine
2013Co-Authors: Lars Ohl, Oliver Pabst, Golo Henning, Stefan Krautwald, S Hardtke, Günter Bernhardt, Reinhold ForsterAbstract:Homeostatic Chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer’s patches depends on the recruitment of CD3 � CD4 � interleukin (IL)-7R � hi cells to sites of future organ development. CD3 � CD4 � IL-7R � hi cells express the Chemokine Receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5 �/ � CCR7 �/ � double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both Receptors in secondary lymphoid organ development. We demonstrate that CD3 � CD4 � IL-7R � hi cells express CXCR5 as well as CCR7 indicating that both Receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5 �/ � CCR7 �/ � mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5 �/ � CCR7 �/ � mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization. Key words
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Chemokine Receptor CXCR5 supports solitary intestinal lymphoid tissue formation b cell homing and induction of intestinal iga responses
Journal of Immunology, 2009Co-Authors: Sarvari Velaga, Reinhold Forster, Heike Herbrand, Michaela Friedrichsen, Tian Jiong, Martina Dorsch, Matthias W Hoffmann, Oliver PabstAbstract:Solitary intestinal lymphoid tissue (SILT) comprises a spectrum of phenotypically diverse lymphoid aggregates interspersed throughout the small intestinal mucosa. Manifestations of SILT range from tiny lymphoid aggregates almost void of mature lymphocytes to large structures dominated by B cells. Large SILT phenotypically resemble a single Peyer’s patch follicle, suggesting that SILT might contribute to intestinal humoral immune responses. In this study, we track the fate of individual SILT in vivo over time and analyze SILT formation and function in Chemokine Receptor CXCR5-deficient mice. We show that, in analogy to Peyer’s patches, formation of SILT is invariantly determined during ontogeny and depends on CXCR5. Young CXCR5-deficient mice completely lack SILT, suggesting that CXCR5 is essential for SILT formation during regular postnatal development. However, microbiota and other external stimuli can induce the formation of aberrant SILT distinguished by impaired development of B cell follicles in CXCR5-deficient mice. Small intestinal transplantation and bone marrow transplantation reveal that defect follicle formation is due to impaired B cell homing. Moreover, oral immunization with cholera toxin or infection with noninvasive Salmonella fail to induce efficient humoral immune responses in CXCR5-deficient mice. Bone marrow transplantation of CXCR5-deficient recipients with wild-type bone marrow rescued B cell follicle formation in SILT but failed to restore full humoral immune responses. These results reveal an essential role of CXCR5 in Peyer’s patch and SILT development and function and indicate that SILT do not fully compensate for the lack of Peyer’s patches in T cell-dependent humoral immune responses.
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Unaltered levels of transplant arteriosclerosis in the absence of the B cell homing Chemokine Receptor CXCR5.
Transplant Immunology, 2008Co-Authors: Stephan Ensminger, Silvija Abele, Bernd M. Spriewald, Martina Ramsperger-gleixner, Michael Weyand, Reinhold ForsterAbstract:Chemokine Receptors and their ligands are crucial for lymphocyte trafficking under both homeostatic and inflammatory conditions. The Chemokine Receptor CXCR5 controls B cell migration and the organization of B cell follicles. The aim of this study was to investigate the impact of CXCR5 on the development of transplant arteriosclerosis. Fully MHC mismatched BALB/c (H2d) donor aortas were transplanted into C57BL/6-CXCR5−/− (H2b), C57BL/6-CXCR5+/− (H2b) or C57BL/6-CXCR5+/+ (H2b) recipients. Grafts were analysed by morphometry and immunofluorescence and intra-graft cytokine mRNA production was analysed by RT-PCR. Transplant arteriosclerosis was evident in CXCR5+/+ and CXCR5+/− mice and only mildly reduced in CXCR5−/− recipients indicating that absence of CXCR5 had no substantial effect on the development of transplant arteriosclerosis. Analysis of the cellular infiltrate of aortic grafts implanted in CXCR5−/− recipients revealed no differences in the number of T-cells, macrophages and B cells as compared to controls. Intra-graft cytokine production showed no significant changes in Th1 (IL-12) and Th2 (IL-4) cytokines as well as in TGF-β and iNOS production. These data suggest that lack of CXCR5 expression by recipient T- and B-cells has little effect on the development of transplant arteriosclerosis.
Xiangyu Chen - One of the best experts on this subject based on the ideXlab platform.
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follicular CXCR5 expressing cd8 t cells curtail chronic viral infection
Nature, 2016Co-Authors: Shiyue Hou, Cheng Liu, Anli Zhang, Qiang Bai, Miao Han, Yu Yang, Gang Wei, Ting Shen, Xinxin Yang, Xiangyu ChenAbstract:During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the Chemokine Receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory Receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.
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follicular CXCR5 expressing cd8 t cells curtail chronic viral infection
Nature, 2016Co-Authors: Ran He, Anli Zhang, Yu Yang, Ting Shen, Xinxin Yang, Xiangyu Chen, Lifan Xu, Pengcheng Wang, Juanjuan Ou, Houjie LiangAbstract:A population of partially exhausted CXCR5+ CD8+ T cells, induced by chronic virus infection and residing in B-cell follicles, is shown to control viral replication. During chronic viral infection, virus-specific CD8+ T cells become exhausted, exhibit poor effector function and lose memory potential1,2,3,4. However, exhausted CD8+ T cells can still contain viral replication in chronic infections5,6,7,8,9, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8+ T cells expressing the Chemokine Receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5+ CD8+ T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory Receptors and exhibited more potent cytotoxicity than the CXCR5− subset. Furthermore, we identified the Id2–E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5+ CD8+ T-cell subset, and its number was inversely correlated with viral load. The CXCR5+ subset showed greater therapeutic potential than the CXCR5− subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8+ T cells that has a pivotal role in the control of viral replication during chronic viral infection.
Gerd Muller - One of the best experts on this subject based on the ideXlab platform.
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immunotherapy of b cell non hodgkin lymphoma by targeting the Chemokine Receptor CXCR5 in a preclinical mouse model
International Journal of Cancer, 2014Co-Authors: Hossein Panjideh, Gerd Muller, Mathias Koch, Frank Wilde, Susanne Scheu, Gerhard Moldenhauer, Martin LippAbstract:Bispecific antibodies are promising agents for immunotherapy. Here, we describe a quadroma-based trifunctional bispecific antibody binding the Chemokine Receptor CXCR5 and the T-cell antigen CD3 that efficiently prevents tumor growth in a mouse B-cell lymphoma model. CXCR5 regulates the tissue homeostasis of mature B cells and is highly expressed on B-cell non-Hodgkin and lymphocyte-predominant Hodgkin lymphoma, as well as on a subset of CD4(+) T cells known as follicular T-helper cells. In vitro, the bispecific CXCR5::CD3 antibody efficiently recruited effector T cells to CXCR5 expressing B cells and induced a co-stimulation-independent activation of CD8(+) and CD4(+) T cells as demonstrated by the de novo expression of CD25 and CD69, and secretion of the cytokines IFN-γ, TNF-α, IL-6 and IL-10 by peripheral blood mononuclear cells. Notably, at low antibody concentrations, CXCR5::CD3 displayed a significantly higher cytotoxic activity against autologous B cells than its parental antibodies or rituximab. In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival. Taken together, our results identify CXCR5 as a promising target for antibody-based therapies in the treatment of B-cell malignancies.
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follicular b helper t cell activity is confined to CXCR5 hi icos hi cd4 t cells and is independent of cd57 expression
European Journal of Immunology, 2006Co-Authors: Ataur Rasheed, Martin Lipp, Hanspeter Rahn, Federica Sallusto, Gerd MullerAbstract:The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (TFH) cells are characterized by high expression of the homeostatic Chemokine Receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5hiICOShi CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting Chemokine CXCL13. CXCR5hiICOShi CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that TFH cells are only distantly related to CXCR5– and CXCR5+ central memory T (TCM) as well as effector memory T (TEM) cells present in the periphery. CXCR5hiICOShi CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636334
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follicular b helper t cell activity is confined to CXCR5 hi icos hi cd4 t cells and is independent of cd57 expression
European Journal of Immunology, 2006Co-Authors: Ataur Rasheed, Martin Lipp, Hanspeter Rahn, Federica Sallusto, Gerd MullerAbstract:The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (T(FH)) cells are characterized by high expression of the homeostatic Chemokine Receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5(hi)ICOS(hi) CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting Chemokine CXCL13. CXCR5(hi)ICOS(hi) CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that T(FH) cells are only distantly related to CXCR5(-) and CXCR5(+) central memory T (T(CM)) as well as effector memory T (T(EM)) cells present in the periphery. CXCR5(hi)ICOS(hi) CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations.
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signal transduction by the Chemokine Receptor CXCR5 structural requirements for g protein activation analyzed by chimeric cxcr1 CXCR5 molecules
Biological Chemistry, 2001Co-Authors: Gerd Muller, Martin LippAbstract:The human Chemokine Receptors CXCR5 and CXCR1 activate signaling pathways via pertussis toxin-sensitive as well as insensitive G proteins. CXCR5 induces Ca2+ signaling and chemotaxis independently of inhibitory G proteins, whereas the same signaling pathways are entirely dependent on inhibitory G proteins for CXCR1. In contrast, activation of the MAP kinase cascade via ERK1/2 is a pertussis toxin-sensitive signaling event for both Receptors. Using chimeric CXCR1/CXCR5 Receptors we investigated structural requirements for the activation of signal transduction pathways by CXCR5. Individual or multiple intracellular domains of CXCR1 were exchanged for the corresponding sequences of CXCR5, leading to Receptors resembling CXCR5 at the cytoplasmic surface to a varying extent. Replacing the second intracellular domain of CXCR1 had a major influence on signaling mediated by inhibitory G proteins, whereas the exchange of the third or carboxy-terminal intracellular domain had only minor effects on signal transduction. Activation of the MAP kinase cascade via ERK1/2 and chemotaxis are largely reduced in chimeras comprising the second intracellular domain of CXCR5, although coupling to inhibitory G proteins is retained in all chimeric Receptors. In summary, these data characterize the contribution of the intracellular domains of CXCR5 to Receptor signaling, thereby disclosing unique structural requirements that modulate G protein coupling by the Receptor.