Horst Blüthmann
Hoffmann-La Roche
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Featured researches published by Horst Blüthmann.
The EMBO Journal | 1998
Çagatay Günes; Rainer Heuchel; Oleg Georgiev; Karl-Heinz Müller; Peter Lichtlen; Horst Blüthmann; Silvia Marino; Adriano Aguzzi; Walter Schaffner
We have shown previously that the heavy metal‐responsive transcriptional activator MTF‐1 regulates the basal and heavy metal‐induced expression of metallothioneins. To investigate the physiological function of MTF‐1, we generated null mutant mice by targeted gene disruption. Embryos lacking MTF‐1 die in utero at approximately day 14 of gestation. They show impaired development of hepatocytes and, at later stages, liver decay and generalized edema. MTF‐1−/− embryos fail to transcribe metallothionein I and II genes, and also show diminished transcripts of the gene which encodes the heavy‐chain subunit of the γ‐glutamylcysteine synthetase, a key enzyme for glutathione biosynthesis. Metallothionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermediates. Accordingly, primary mouse embryo fibroblasts lacking MTF‐1 show increased susceptibility to the cytotoxic effects of cadmium or hydrogen peroxide. Thus, MTF‐1 may help to control metal homeostasis and probably cellular redox state, especially during liver development. We also note that the MTF‐1 null mutant phenotype bears some similarity to those of two other regulators of cellular stress response, namely c‐Jun and NF‐κB (p65/RelA).
Journal of Immunology | 2000
Tobias Litzenburger; Horst Blüthmann; Patricia Morales; Danielle Pham-Dinh; André Dautigny; Hartmut Wekerle; Antonio Iglesias
We explored mechanisms involved in B cell self-tolerance against brain autoantigens in a double-transgenic mouse model carrying the Ig H-chain (introduced by gene replacement) and/or the L-chain κ (conventional transgenic) of the mAb 8.18C5, specific for the myelin oligodendrocyte glycoprotein (MOG). Previously, we demonstrated that B cells expressing solely the MOG-specific Ig H-chain differentiate without tolerogenic censure. We show now that double-transgenic (THκmog) B cells expressing transgenic Ig H- and L-chains are subjected to receptor editing. We show that in adult mice carrying both MOG-specific Ig H- and L-chains, the frequency of MOG-binding B cells is not higher than in mice expressing solely the transgenic Ig H-chain. In fact, in THκmog double-transgenic mice, the transgenic κmog L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2− mice, differentiation of THκmog B cells is blocked at an immature stage (defined by the B220lowIgMlowIgD− phenotype), reflecting interaction of the autoreactive B cells with a local self-determinant. The tolerogenic structure in the bone marrow is not classical MOG, because back-crossing THκmog mice into a MOG-deficient genetic background does not lead to an increase in the proportion of MOG-binding B cells. We propose that an as yet undefined self-Ag distinct from MOG cross-reacts with the THκmog B cell receptor and induces editing of the transgenic κmog L-chain in early immature B cells without affecting the pathogenic potential of the remaining MOG-specific B cells. This phenomenon represents a particular form of chain-specific split tolerance.
Journal of Biological Chemistry | 1996
David Lembo; Paola Ricciardi-Castagnoli; Gottfried Alber; Laurence Ozmen; Santo Landolfo; Horst Blüthmann; Zlatko Dembic; Serguei V. Kotenko; Jeffry R. Cook; Sidney Pestka; Gianni Garotta
Studies of hamster-human and mouse-human somatic fibroblast hybrids and transfected mouse fibroblasts have demonstrated that signaling through the human interferon-γ receptor (hu-IFN-γR) requires the formation of a complex consisting of ligand (IFN-γ), a ligand binding receptor chain (IFN-γR1), and a signal transducing receptor chain (IFN-γR2). To date, the ability of this receptor complex to transduce the full repertoire of biological signals has been difficult to assess due to the limited number of activities that IFN-γ can exert on fibroblasts. The current report assesses the ability of hu-IFN-γR chains to transduce signals in the absence of background human gene products by expressing hu-IFN-γR2 in a transformed macrophage cell line (F10/96) derived from a hu-IFN-γR1 transgenic mouse. Our results indicate that F10/96 clones expressing both human receptor proteins bind hu-IFN-γ with an affinity comparable to that of human cells. Binding of either human or mouse IFN-γ to its respective receptor elicits classic IFN-γ responses such as up-regulation of major histocompatibility complex antigens, enhanced expression of IRF-1, and increased production of NO2− radicals, interleukin-6, tumor necrosis factor-α, and granulocyte macrophage-colony stimulating factor. However, hu-IFN-γ could not fully protect the clones from cytopathic effects of encephalomyocarditis virus and vesicular stomatitis virus while mo-IFN-γ could. These results demonstrate that while co-expression of hu-IFN-γR1 and hu-IFN-γR2 is necessary and sufficient for most IFN-γ-induced responses, it is not sufficient to confer a generalized antiviral state. These findings further suggest that additional species-specific accessory factor(s) are necessary for full signaling potential through the IFN-γ receptor complex. The nature and potential role of such factors in IFN-γR signaling is discussed.
Archive | 1999
Çagatay Günes; Rainer Heuchel; Oleg Georgiev; Karl-Heinz Müller; Silvia Marino; Adriano Aguzzi; Horst Blüthmann; Walter Schaffner
The metal regulatory transcription factor 1 (MTF-1) is a highly conserved transcriptional activator (Radtke et al., 1993; Heuchel et al., 1994; Radtke et al., 1995). We previously cloned mouse and human MTF-1, which share a 93% identity in amino acid sequence (Radtke et al., 1993; Brugnera et al., 1994). MTF-1 contains six zinc fingers of the C2H2-type as a DNA binding domain and at least three distinct domains responsible for transcriptional activation (Fig. 1). It binds to a number of metal responsive elements (MREs) present in the promoter regions of metallothionein genes I and II (MT-I and MT-II) and regulates their expression.
Archive | 1990
Horst Blüthmann; Michael Steinmetz; Harald von Boehmer
During T cell development in the thymus genes coding for the α and β chains of the T cell receptor (TCR) are assembled from the respective gene segments (for review see Kronenberg et al. 1986). Combinatorial joining of different α and β gene segments leads to a diverse spectrum of TCR specificities on developing thymocytes which are positively selected for self-MHC recognition and negatively for self tolerance during further maturation (Fink and Bevan 1978, Zinkernagel et al. 1978). The enormous diversity of the T cell repertoire, however, makes it difficult to follow a T cell with a given specificity during T cell development.
Current Topics in Microbiology and Immunology | 1989
Harald von Boehmer; Horst Blüthmann; Hung Sia Teh; Bernadette Scott
It is believed that in scid mice the rearrangement process required for the expression of immunoglobulin (Ig) and T cell receptors (TCR) genes is defective (Bosma et al., 1983, Schuler et al., 1986). The ability to exploit this defect would provide unique opportunities to study the control of lymphocyte development by receptors encoded by rearranging gene segments.
Nature | 1988
Pawel Kisielow; Horst Blüthmann; Uwe D. Staerz; Michael Steinmetz; Harald von Boehmer
Nature | 1988
Hung Sia Teh; Pawel Kisielow; Bernadette Scott; Hiroyuki Kishi; Yasushi Uematsu; Horst Blüthmann; Harald von Boehmer
Nature | 1988
Pawel Kisielow; Hung Sia Teh; Horst Blüthmann; Harald von Boehmer
Nature | 1989
Bernadette Scott; Horst Blüthmann; Hung Sia Teh; Harald von Boehmer