Bernd Arnold

German Cancer Research Center, Heidelburg, Baden-Württemberg, Germany

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Publications (129)1190.96 Total impact

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    ABSTRACT: L1CAM is overexpressed in many human cancers, confers bad prognosis and augments cell motility, invasion and metastasis. Results from xenograft mouse models suggested that L1CAM antibodies might be promising tools for cancer therapy. Here we generated human L1CAM-transgenic mice to study therapeutic efficacy and putative side effects in a model system. We established three transgenic lines (M2, M3, F4) expressing the human L1CAM transgene in brain, kidney and colon with decreasing intensity (M2,M3>F4). The expression pattern was similar to that of L1CAM in humans. No interference of the transgene with the expression of endogenous L1CAM was observed. Immunohistochemical analysis revealed correct expression of the transgene in mouse cortex and collective duct of the kidney. Injection of (125) I-labelled L1CAM antibodies resulted in specific enrichment in the kidney but not in the brain. The injection of the therapeutic anti human L1CAM mAb L1-9.3/2a into transgenic mice even at high doses did not cause behavioral changes or other side effects. Similar results were obtained using a mouse specific L1CAM mAb in normal mice. Tumor therapy experiments were performed using syngeneic mouse tumor cells (RET melanoma and Panc02 pancreatic adenocarcinoma) transduced with human L1CAM. MAb L1-9.3/2a efficiently and specifically attenuated local tumor growth in both model systems without apparent side effects. The therapeutic effect was dependent on immune effector mechanisms. Analysis of Panc02-huL1CAM tumors after therapy showed elevated levels of EGF and evidence of immune-induced epithelial-mesenchymal transition. The results suggest that our transgenic mice are valuable tools to study L1CAM-based antibody therapy. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; · 6.20 Impact Factor
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    ABSTRACT: The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop-cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histological characteristics of human HCC established a functional vasculature by cooption, remodeling and angiogenic expansion of the pre-existing sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with Sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1 and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies.
    Cancer Research 06/2014; · 9.28 Impact Factor
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    ABSTRACT: Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.
    Journal of Neuroimmunology 06/2014; 12(6):e1001874. · 2.79 Impact Factor
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    ABSTRACT: The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response upon engagement with damage-associated molecular pattern molecules (DAMPs) such as S100 proteins and high-mobility group box 1 (HMGB1). Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2−/− mouse model, a prototype model of inflammation-driven HCC formation, which mimics the human pathology. Mdr2−/− Rage−/− (dKO) mice developed smaller and fewer HCCs than Mdr2−/− mice. Interestingly, although in preneoplastic Mdr2−/− livers RAGE ablation did not affect the onset of inflammation, premalignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2-Cyclin D1-dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the choline deficient ethionine-supplemented dietary regime. Conclusion: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis. (Hepatology 2013)
    Hepatology 07/2013; 58(1). · 11.19 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC. The murine inducible albumin-SV40-large T-antigen model and two tissue microarrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b. LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 μm in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63-95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion. In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.
    Liver international: official journal of the International Association for the Study of the Liver 06/2013; · 4.41 Impact Factor
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    ABSTRACT: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p < 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-κB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-κB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p < 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
    The Journal of Immunology 05/2013; · 5.36 Impact Factor
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    ABSTRACT: BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4+ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naive T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE. FINDINGS: Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE. CONCLUSIONS: DC are sufficient as APC to effectively drive the differentiation of naive myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.
    Journal of Neuroinflammation 10/2012; 9(1):248. · 4.90 Impact Factor
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    ABSTRACT: Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF.
    Cell Reports 08/2012; 2(3):478-87. · 7.21 Impact Factor
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    ABSTRACT: Interleukin-7 (IL-7) is a major survival factor for mature T cells. Therefore, the degree of IL-7 availability determines the size of the peripheral T cell pool and regulates T cell homeostasis. Here we provide evidence that IL-7 also regulates the homeostasis of intestinal epithelial cells (IEC), colon function and the composition of the commensal microflora. In the colon of T cell-deficient, lymphopenic mice, IL-7-producing IEC accumulate. IEC hyperplasia can be blocked by IL-7-consuming T cells or the inactivation of the IL-7/IL-7R signaling pathway. However, the blockade of the IL-7/IL-7R signaling pathway renders T cell-deficient mice more sensitive to chemically-induced IEC damage and subsequent colitis. In summary, our data demonstrate that IL-7 promotes IEC hyperplasia under lymphopenic conditions. Under non-lymphopenic conditions, however, T cells consume IL-7 thereby limiting IEC expansion and survival. Hence, the degree of IL-7 availability regulates both, T cell and IEC homeostasis.
    PLoS ONE 02/2012; 7(2):e31939. · 3.53 Impact Factor
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    ABSTRACT: In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.
    Proceedings of the National Academy of Sciences 01/2012; 109(5):1631-6. · 9.81 Impact Factor
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    ABSTRACT: Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified junctional adhesion molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C(-/-) mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.
    Cancer Research 06/2011; 71(12):4096-105. · 9.28 Impact Factor
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    ABSTRACT: Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a key enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or 'degradome' of MMP-9 and found many systemic autoantigens as novel intracellular gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6(lpr/lpr) mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced lymphadenopathy and splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of 'double negative' T cells, B cells and myeloid cells. In addition, higher autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE autoantigens U1snRNP A and ribosomal protein P0 were hardly recognized by plasma samples of both B6(lpr/lpr).MMP-9⁻/⁻ and B6(lpr/lpr).MMP-9+/+ mice, pointing to a destruction of B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of MMP inhibitors in autoimmune lymphoproliferative syndrome (ALPS) and SLE.
    Journal of Autoimmunity 03/2011; 36(3-4):239-52. · 7.02 Impact Factor
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    ABSTRACT: Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 (Stab1–/– Stab2–/– mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, Stab1–/– Stab2–/– mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation into WT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of Stab1–/– Stab2–/– mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in Stab1–/– Stab2–/– mice but not in either Stab1–/– or Stab2–/– mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs.
    The Journal of clinical investigation 02/2011; 121(2):703-14. · 15.39 Impact Factor
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    ABSTRACT: Meiosis is a crucial process for the production of functional gametes. However, the biological significance of many genes expressed during the meiotic phase remains poorly understood, mainly because of the lethal phenotypes of the knockout mice. Functional analysis of such genes using the conditional knockout approach is hindered by the lack of suitable Cre transgenic lines. We describe here the generation of transgenic mice expressing Cre recombinase under the control of the meiotic Spo11 gene. Using LacZ-R26(loxP) and EYFP-R26(loxP) reporter mice, we show the specific expression and activity of Cre during meiosis in males and females. Spo11(Cre) mice were then crossed with floxed Nbs1 and JAM-C mice to produce conditional knockouts. A strong reduction of Nbs1 and JAM-C protein levels was found in the testis. Although Nbs1-deleted mice developed minor gonadal abnormalities, JAM-C-knockout mice showed a spermiogenetic arrest, as previously described for the null mice. These results provide strong evidence that Spo11(Cre) transgenic mice represent a powerful tool for deleting genes of interest specifically in meiotic and/or in postmeiotic germ cells.
    Journal of Cell Science 01/2011; 124(Pt 1):91-9. · 5.33 Impact Factor
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    ABSTRACT: Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.
    The Journal of Immunology 11/2010; 185(12):7518-26. · 5.36 Impact Factor
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    ABSTRACT: IL-7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL-7 production. To study Il7 gene regulation in vivo, we generated a novel IL-7-reporter mouse, which allows the non-invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL-7-producing cells. With these IL-7-reporter mice, we identify thymus, skin and intestine as major sources of IL-7 in vivo. Importantly, we show that IFN-gamma and the commensal microflora promote steady-state IL-7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN-gamma signaling in intestinal epithelial cells strongly reduces their IFN-gamma-driven IL-7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN-gamma production by lymphocytes, which in turn promotes epithelial cell IL-7 production and the survival of IL-7-dependent lymphocytes.
    European Journal of Immunology 09/2010; 40(9):2391-400. · 4.52 Impact Factor
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    ABSTRACT: The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability.
    Proceedings of the National Academy of Sciences 08/2010; 107(35):15529-34. · 9.81 Impact Factor
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    ABSTRACT: The central paradigm says that during inflammation, after completing their function, granulocytes die apoptotically in periphery to avoid destruction of self-tissues. Here we aimed to investigate the kinetic aspect of inflammatory leukocyte apoptosis and verify whether apart from neutrophils also other inflammatory leukocytes numerously undergo apoptosis. We observed that in physiological conditions, less than 7% of either resident peritoneal macrophages or lymphocytes die apoptotically. The studies on a model of acute zymosan-induced peritoneal inflammation revealed that there are two waves of inflammatory leukocyte apoptosis. The first wave corresponds to the time of maximal neutrophil accumulation in peritoneum (6 h) and the apoptotic death indeed concerns mostly neutrophils (over 30% of those cells), but also more macrophages die at this time (>10%). The second wave (at 3 days) concerns mostly macrophages (20% versus 3–6% for other populations) and coincides with the resolution of inflammation and the dominant presence of macrophages. In contrast, numbers of apoptotic T (1–3%) and B (~5%) cells do not significantly change during the whole peritonitis. The two waves of apoptosis concur with an increase of caspase-8, -9 and -3 at the transcript and activity levels. The apoptosis inducer TNF-α is produced only during first hours while nitric oxide throughout all inflammation. Moreover, during the whole course of peritonitis the expression of pro-apoptotic Bax dominates over anti-apoptotic Bcl-2. In conclusion, we characterized kinetics of apoptotic death of inflammatory leukocytes during acute peritoneal inflammation and revealed that both phagocyte populations (neutrophils and macrophages) die numerously in peritoneum.
    Immunobiology 06/2010; · 2.81 Impact Factor
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    ABSTRACT: Functional inactivation of self-reactive T lymphocytes contributes to the maintenance of immunologic self-tolerance. At the same time, tolerance induction limits immune responses against tumors expressing tolerizing self-antigens. Some cancer therapies include the adoptive transfer of tumor-reactive T lymphocytes into lymphopenic patients. Lymphopenia provides an activation signal to T lymphocytes, which undergo lymphopenia-induced proliferation (LIP), acquire effector functions, and reject tumors. However, it is so far unknown to which extent LIP may result in reversal of established antigen-specific CD8 T-cell tolerance. Here, we report that neonatally induced dominant CD8 T-cell tolerance remained stable under lymphopenic conditions also in the presence of systemic inflammation induced by Toll-like receptor ligands. However, when lymphopenic recipients were irradiated, the tolerant status was lost, because CD8 T cells acquired effector functions in an interleukin-15-dependent fashion and efficiently rejected tumors. In conclusion, we show that lymphopenia is not sufficient to break CD8 T-cell tolerance. Furthermore, we demonstrate that pretreatment regimens are crucial to circumvent this problem and to optimize adoptive T-cell therapy.
    Blood 03/2010; 115(11):2196-202. · 9.78 Impact Factor
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    ABSTRACT: Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10(-/-) mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. Impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival. This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. Therefore alternative therapeutic approaches to an isoleucine-restricted diet are required.
    EMBO Molecular Medicine 02/2010; 2(2):51-62. · 7.80 Impact Factor

Publication Stats

8k Citations
1,190.96 Total Impact Points

Institutions

  • 1982–2014
    • German Cancer Research Center
      • Division of Molecular Immunology
      Heidelburg, Baden-Württemberg, Germany
  • 2005–2013
    • Universität Heidelberg
      • • Institute of Clinical Chemistry
      • • Department of Molecular Biology
      • • Institute of Medical Psychology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2009
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2006–2009
    • Jagiellonian University
      • • Institute of Zoology
      • • Department of Evolutionary Immunology
      Kraków, Lesser Poland Voivodeship, Poland
    • Max Planck Institute of Neurobiology
      München, Bavaria, Germany
  • 2000–2003
    • KU Leuven
      • • Department of Microbiology and Immunology
      • • Rega Institute for Medical Research
      Leuven, VLG, Belgium
  • 1992–1999
    • Centre d'Immunologie de Marseille-Luminy
      Marsiglia, Provence-Alpes-Côte d'Azur, France