Interferons are a family of cytokine mediators involved in the cellular immune response, ie again... more Interferons are a family of cytokine mediators involved in the cellular immune response, ie against viral infections or amplifying antigen presentation to specific T cells. Recombinant human IFN-alpha±2a and IFN-alpha±2b are used for the treatment of several diseases, while recombinant forms of IFN-beta1a and IFN-beta1b are only certified for the treatment of multiple sclerosis. Recently, we have reported the generation of a novel cell-based assay to quantify murine IFNs. The assay consists of a murine type I IFN induction phase, which ...
As recommendations for specific pathogen-free housing change, mouse facilities need to re-derive ... more As recommendations for specific pathogen-free housing change, mouse facilities need to re-derive their colonies repeatedly in order to eliminate specified bacteria or viruses. This paper describes the establishment of a new mouse facility using as starting point a small colony of CD-1 mice colonized with the Charles River altered Schaedler flora (CRASF®) housed in individually ventilated cages (IVCs). The import of new strains was performed exclusively via embryo transfer using CD-1 mice as recipients. The integrity of the CRASF® in caecum samples of the original CD-1 colony and of three inbred mouse lines imported into the colony was proven by a quantitative realtime polymerase chain reaction approach. Furthermore, we searched for bacterial contaminants in the gut flora using non-specific 16S rRNA primers. The bacterial sequences found were closely related to but not exclusively sequences of altered Schaedler flora (ASF) members, suggesting that the ASF is heterogeneous rather than...
Vascular cellular adhesion molecule (VCAM)-1 is a membrane-bound cellular adhesion molecule that ... more Vascular cellular adhesion molecule (VCAM)-1 is a membrane-bound cellular adhesion molecule that mediates adhesive interactions between hematopoietic progenitor cells and stromal cells in the bone marrow (BM) and between leukocytes and endothelial as well as dendritic cells. Since VCAM-1–deficient mice die embryonically, conditional VCAM-1 mutant mice were generated to analyze the in vivo function of this adhesion molecule. Here we show that interferon-induced Cre-loxP–mediated deletion of the VCAM-1 gene after birth efficiently ablates expression of VCAM-1 in most tissues like, for example, BM, lymphoid organs, and lung, but not in brain. Induced VCAM-1 deficiency leads to a reduction of immature B cells in the BM and to an increase of these cells in peripheral blood but not in lymphoid organs. Mature recirculating B cells are reduced in the BM. In a migration assay, the number of mature B cells that appears in the BM after intravenous injection is decreased. In addition, the humor...
Absence ofβ2integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary... more Absence ofβ2integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary immunodeficiency syndrome. Although extensivein vitrowork has established an essential function ofβ2integrins in adhesive and signaling properties for cells of the innate and adaptive immune system, their respective participation in an altered adaptive immunity in LAD1 patients are complex and only partly understoodin vivo. Therefore, we investigated adaptive immune responses towards different T-dependent antigens in a murine LAD1 model ofβ2integrin-deficiency (CD18−/−). CD18−/−mice generated only weak IgG responses after immunization with tetanus toxoid (TT). In contrast, robust hapten- and protein-specific immune responses were observed after immunization with highly haptenated antigens such as (4-hydroxy-3-nitrophenyl)21acetyl chickenγglobulin (NP21-CG), even though regularly structured germinal centers with specificity for the defined antigens/haptens in CD18−/−mice remained absent....
Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of ... more Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of hematopoietic precursor cells and mast cells. Somatic point mutations of the receptor that constitutively activate kit signaling are associated with mastocytosis and various hematopoietic malignancies. We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter. Expression of the mutant kit in cells of adult mice, including hematopoietic precursors, caused severe mastocytosis with 100% penetrance at young age frequently associated with additional hematopoietic (mostly B lineage–derived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower kinetics. Embryonic expression led to a hyperp...
The cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of... more The cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of murine, but not human myelomonocytic cell lines by radioligand binding. cDNA clones encoding the receptor were isolated from a murine T helper cell cDNA library. TSLP receptor (TSLPR) is a member of the hematopoietin receptor family. Transfection of TSLPR cDNA resulted in only low affinity binding. Cotransfection of the interleukin 7 (IL-7)Rα chain cDNA resulted in conversion to high affinity binding. TSLP did not activate cells from IL-7Rα−/− mice, but did activate cells from γc−/− mice. Thus, the functional TSLPR requires the IL-7Rα chain, but not the γc chain for signaling.
Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. ... more Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. Recent in vitro studies have suggested that IL-4 derived from non T helper (Th) cells, in particular from mast cells and basophils, may be essential for triggering of IL-4 expression in Th cells and may directly contribute to IgE isotype switch induction. Here, we have generated mice carrying a functional IL-4 gene only in Th cells or non-Th cells, respectively, by reconstitution of IL-4-deficient mice (IL-4T mice) with CD4+ or CD4- spleen cells from congenic wild-type animals. In mice in which only CD4+ cells are able to express IL-4, antigen-specific IgE is produced in a T cell-dependent immune response. Thus, induction of IL-4 expression in Th cells can occur in the absence of IL-4 from non-Th cells, which suggests that at least some Th cells can express IL-4 in response to another signal which has yet to be identified. No IgE is detectable, however, in mice in which only CD4- cells c...
Interferons are a family of cytokine mediators involved in the cellular immune response, ie again... more Interferons are a family of cytokine mediators involved in the cellular immune response, ie against viral infections or amplifying antigen presentation to specific T cells. Recombinant human IFN-alpha±2a and IFN-alpha±2b are used for the treatment of several diseases, while recombinant forms of IFN-beta1a and IFN-beta1b are only certified for the treatment of multiple sclerosis. Recently, we have reported the generation of a novel cell-based assay to quantify murine IFNs. The assay consists of a murine type I IFN induction phase, which ...
As recommendations for specific pathogen-free housing change, mouse facilities need to re-derive ... more As recommendations for specific pathogen-free housing change, mouse facilities need to re-derive their colonies repeatedly in order to eliminate specified bacteria or viruses. This paper describes the establishment of a new mouse facility using as starting point a small colony of CD-1 mice colonized with the Charles River altered Schaedler flora (CRASF®) housed in individually ventilated cages (IVCs). The import of new strains was performed exclusively via embryo transfer using CD-1 mice as recipients. The integrity of the CRASF® in caecum samples of the original CD-1 colony and of three inbred mouse lines imported into the colony was proven by a quantitative realtime polymerase chain reaction approach. Furthermore, we searched for bacterial contaminants in the gut flora using non-specific 16S rRNA primers. The bacterial sequences found were closely related to but not exclusively sequences of altered Schaedler flora (ASF) members, suggesting that the ASF is heterogeneous rather than...
Vascular cellular adhesion molecule (VCAM)-1 is a membrane-bound cellular adhesion molecule that ... more Vascular cellular adhesion molecule (VCAM)-1 is a membrane-bound cellular adhesion molecule that mediates adhesive interactions between hematopoietic progenitor cells and stromal cells in the bone marrow (BM) and between leukocytes and endothelial as well as dendritic cells. Since VCAM-1–deficient mice die embryonically, conditional VCAM-1 mutant mice were generated to analyze the in vivo function of this adhesion molecule. Here we show that interferon-induced Cre-loxP–mediated deletion of the VCAM-1 gene after birth efficiently ablates expression of VCAM-1 in most tissues like, for example, BM, lymphoid organs, and lung, but not in brain. Induced VCAM-1 deficiency leads to a reduction of immature B cells in the BM and to an increase of these cells in peripheral blood but not in lymphoid organs. Mature recirculating B cells are reduced in the BM. In a migration assay, the number of mature B cells that appears in the BM after intravenous injection is decreased. In addition, the humor...
Absence ofβ2integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary... more Absence ofβ2integrins (CD11/CD18) leads to leukocyte-adhesion deficiency-1 (LAD1), a rare primary immunodeficiency syndrome. Although extensivein vitrowork has established an essential function ofβ2integrins in adhesive and signaling properties for cells of the innate and adaptive immune system, their respective participation in an altered adaptive immunity in LAD1 patients are complex and only partly understoodin vivo. Therefore, we investigated adaptive immune responses towards different T-dependent antigens in a murine LAD1 model ofβ2integrin-deficiency (CD18−/−). CD18−/−mice generated only weak IgG responses after immunization with tetanus toxoid (TT). In contrast, robust hapten- and protein-specific immune responses were observed after immunization with highly haptenated antigens such as (4-hydroxy-3-nitrophenyl)21acetyl chickenγglobulin (NP21-CG), even though regularly structured germinal centers with specificity for the defined antigens/haptens in CD18−/−mice remained absent....
Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of ... more Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of hematopoietic precursor cells and mast cells. Somatic point mutations of the receptor that constitutively activate kit signaling are associated with mastocytosis and various hematopoietic malignancies. We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter. Expression of the mutant kit in cells of adult mice, including hematopoietic precursors, caused severe mastocytosis with 100% penetrance at young age frequently associated with additional hematopoietic (mostly B lineage–derived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower kinetics. Embryonic expression led to a hyperp...
The cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of... more The cellular receptor for murine thymic stromal lymphopoietin (TSLP) was detected in a variety of murine, but not human myelomonocytic cell lines by radioligand binding. cDNA clones encoding the receptor were isolated from a murine T helper cell cDNA library. TSLP receptor (TSLPR) is a member of the hematopoietin receptor family. Transfection of TSLPR cDNA resulted in only low affinity binding. Cotransfection of the interleukin 7 (IL-7)Rα chain cDNA resulted in conversion to high affinity binding. TSLP did not activate cells from IL-7Rα−/− mice, but did activate cells from γc−/− mice. Thus, the functional TSLPR requires the IL-7Rα chain, but not the γc chain for signaling.
Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. ... more Interleukin 4 (IL-4) is essential for the induction of immunoglobulin E (IgE) responses in mice. Recent in vitro studies have suggested that IL-4 derived from non T helper (Th) cells, in particular from mast cells and basophils, may be essential for triggering of IL-4 expression in Th cells and may directly contribute to IgE isotype switch induction. Here, we have generated mice carrying a functional IL-4 gene only in Th cells or non-Th cells, respectively, by reconstitution of IL-4-deficient mice (IL-4T mice) with CD4+ or CD4- spleen cells from congenic wild-type animals. In mice in which only CD4+ cells are able to express IL-4, antigen-specific IgE is produced in a T cell-dependent immune response. Thus, induction of IL-4 expression in Th cells can occur in the absence of IL-4 from non-Th cells, which suggests that at least some Th cells can express IL-4 in response to another signal which has yet to be identified. No IgE is detectable, however, in mice in which only CD4- cells c...
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Papers by Werner Muller