Christoph Mueller | University of Bern (original) (raw)

Papers by Christoph Mueller

Cell Death and Differentiation, 2001

Intraepithelial lymphocytes (IEL) of the small murine bowel represent a unique population of most... more Intraepithelial lymphocytes (IEL) of the small murine bowel represent a unique population of mostly CD8 + T lymphocytes that reside within the epithelial cell layer of the intestinal mucosa. The close interaction with epithelial cells appears to be crucial for IEL survival since isolation and ex vivo culture induces massive apoptosis in this lymphocyte population. Here, we provide evidence that this form of IEL cell death may be mediated at least in part by endogenously produced glucocorticoids since adrenalectomy or treatment of mice with a glucocorticoid receptor antagonist significantly enhanced ex vivo survival of IEL. We further demonstrate that ex vivo activation of IEL induces upregulation of antiapoptotic gene products, compensates for the lack of survival cytokines and rescues from apoptotic cell death. Thus, similar to thymocytes and T cell hybridomas, IEL survival may be regulated by the antagonistic action of TCR activation and glucocorticoids. Cell Death and Differentiation (2001) 8, 706 ± 714.

Journal of Experimental Medicine, 2004

Survivin has received great attention due to its expression in many human tumors and its potentia... more Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle–dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restri...

Mucosal immunology, 2016

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side ef... more Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumo...

Nature Communications, 2016

After systemic infection of mice with 10 4 PFU of lymphocytic choriomeningitis virus (LCMV), infe... more After systemic infection of mice with 10 4 PFU of lymphocytic choriomeningitis virus (LCMV), infected cells are detected simultaneously in various organs, including spleen and intestinal mucosa. Most notably, virus-infected cells are also present among CD11c ؉ dendritic cells in the subepithelial area of the small intestinal mucosa. Some of these virus-infected cells are in close spatial association with intestinal intraepithelial lymphocytes (IEL). Therefore, we compared virus-specific cytotoxic activity of CD8 splenocytes with that of IEL subsets. While ex vivo isolated TCR␣␤ ؉ CD8␣␣ ؉ IEL exert only minimal virus-specific cytotoxicity, maximum specific killing mediated by TCR␣␤ ؉ CD8␣␤ ؉ IEL on day 8 postinfection exceeds maximum cytotoxic activity observed with CD8 splenocytes when assessed in vitro. Maximum cytotoxic activity of IEL is preceded by peak perforin and granzyme B mRNA expression in IEL around day 6 postinfection, suggesting a recent activation in situ. The antivirus cytotoxicity of in vivo primed IEL is further demonstrated by the protection from virus production in the spleen of mice infected with LCMV 10 h before adoptive cell transfer. These data indicate a potent priming of LCMV-specific IEL in situ after systemic LCMV infection and suggest that cytotoxic IEL markedly contribute to the elimination of virus-infected cells in the intestinal mucosa.

American Journal of …, 2005

To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechani... more To study the specific role of transmembrane tumor necrosis factor (TmTNF) in host defense mechanisms against bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis infections, we compared the immune responses of TNF/lymphotoxin (LT)- / mice expressing a noncleavable ...

Inflammatory intestinal diseases, 2018

The prospective, observational Swiss Eosinophilic Esophagitis Cohort Study (SEECS) was set up in ... more The prospective, observational Swiss Eosinophilic Esophagitis Cohort Study (SEECS) was set up in 2015 with the following goals in mind: (1) to provide up-to-date epidemiologic data; (2) to assess the appropriateness of care; (3) to evaluate the psychosocial impact; and (4) to foster translational research projects. Data capture relies on validated instruments to assess disease activity and focuses on epidemiologic variables and biosamples (esophageal biopsies and blood specimens). An annual inclusion of 70 new patients with eosinophilic esophagitis (EoE) or proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is intended. We herein describe the SEECS cohort profile. The SEECS includes adult patients (age ≥18 years) with EoE or PPI-REE diagnosed according to published criteria. After inclusion, the patients are typically seen once a year for a clinical and endoscopic/histologic follow-up examination. Data are captured using validated questionnaires. Biosamples from pati...

The Journal of allergy and clinical immunology, Jan 5, 2017

Exaggerated TSLP production and infiltration of basophils are associated with the pathogenesis of... more Exaggerated TSLP production and infiltration of basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development of food allergies. While TSLP and basophils have been implicated to promote food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited basophils guide the progression of allergic inflammation in the skin to distant mucosal sites such as the gastrointestinal tract are poorly understood. We sought to test the role of basophil-intrinsic IL-4 production in TH2 sensitization to food antigens in the skin and effector food allergic responses in the gut. Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intra-gastric antigen challenge to induce IgE-mediated food allergy. The requirement for basophil-derived IL-4 production for TH2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by co-culture experi...

Cell Host & Microbe, 2016

Highlights d Acute Salmonella infection elicits IFN-g responses that remain during antibiotic the... more Highlights d Acute Salmonella infection elicits IFN-g responses that remain during antibiotic therapy d IFN-g sustains STAT1 and cytokines, while blocking IL-22/ REGIII defenses d T-and NK cell-derived IFN-g delays the resolution of mucosal pathology d IFN-g could be targeted for accelerating resolution

Gastroenterology, Sep 30, 2004

Summary In this study, we addressed the role of tumor necrosis factor (TNF)- a and lymphotoxin (L... more Summary In this study, we addressed the role of tumor necrosis factor (TNF)- a and lymphotoxin (LT)- a in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF- a and LT- a ) relevant to disease development. After adoptive transfer of TNF 1 / 1 CD4 1 CD45RB hi splenocytes into TNF

The Veterinary record, Jan 12, 1997

The tumour-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococco... more The tumour-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune-mediated processes. Parasite-mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS)induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT-PCR. Colitis severity was assessed (by board-certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi-quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS-induced gut inflammation by concomitant E. multilocularis infection, which correlated with down-regulation of T helper type 1 (Th1)/Th17 T-cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS-induced gut inflammation upon down-regulation of Th1/Th17 cytokine expression and attenuation of CD11b + cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS-induced colitis in mice by attenuating Th1/Th17-mediated immune reactions.

The contribution of a transmembrane (Tm) form of TNF to protective immunity against Mycobacterium... more The contribution of a transmembrane (Tm) form of TNF to protective immunity against Mycobacterium bovis bacillus Calmette-Guérin (BCG) was studied in transgenic (tg) mice expressing a noncleavable Tm TNF but lacking the TNF/lymphotoxin-␣ (LT-␣) locus (Tm TNF tg mice). These mice were as resistant to BCG infection as wild-type mice, whereas TNF/LT-␣ ؊/؊ , TNF ؊/؊ , and LT-␣ ؊/؊ mice succumbed. Tm TNF tg mice developed granulomas of smaller size but at 2-to 4-fold increased frequencies compared with wild-type mice. Granulomas were mainly formed by monocytes and activated macrophages expressing Tm TNF mRNA and accumulating acid phosphatase. NO synthase 2 activation as a key macrophage bactericidal mechanism was low during the acute phase of infection in Tm TNF tg mice but was still sufficient to limit bacterial growth and increased in late infection. While infection with virulent Mycobacterium tuberculosis resulted in very rapid death of TNF/LT-␣ ؊/؊ mice, it also resulted in survival of Tm TNF tg mice which presented an increase in the number of CFU in spleen (5-fold) and lungs (10-fold) as compared with bacterial load of wild-type mice. In conclusion, the Tm form of TNF induces an efficient cell-mediated immunity and total resistance against BCG even in the absence of LT-␣ and secreted TNF. However, Tm TNF-mediated protection against virulent M. tuberculosis infection can also be efficient but not as strong as in BCG infection, in which cognate cellular interactions may play a more predominant role in providing long-term surveillance and containment of BCG-infected macrophages.

Frontiers in immunology, 2018

Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoi... more Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated coli...

Soluble (sTNF) and transmembrane (tmTNF) forms of TNFalpha (TNF) have distinct proinflammatory ef... more Soluble (sTNF) and transmembrane (tmTNF) forms of TNFalpha (TNF) have distinct proinflammatory effects. We investigated whether tmTNF altered the synthesis of some proinflammatory proteins involved in atherothrombosis, in murine aortas and aortic endothelial cells (MAEC). Samples were obtained from wild-type (WT) mice and TNF-deficient mice that express a mutated non cleavable tmTNF transgene (tmTNFnc). The levels of secreted MCP-1, RANTES, IL-6, PAI-1, soluble ICAM-1, and soluble TNF receptor type 1 (TNFR1; CD120a) antigens, MMP-9 activity and of cell surface ICAM-1 were not significantly different between the two types of MAEC. The magnitude of endotoxin-stimulated production of RANTES, MCP-1 and IL-6 was similar in the two types of cells. Of note, the amount of synthesized TNF receptor type 2 (TNFR2; CD120b), measured by its secreted (in aorta and MAEC), intracellular and mRNA levels (in MAEC), was significantly 4-fold lower in tmTNFnc than in WT mice, both in basal and endotoxin-stimulated conditions. A neutralizing anti-TNF antibody or the recombinant murine TNF did not modify the magnitude of the difference in TNFR2 production between the two types of cells, suggesting a preponderant role of tmTNF in the down-regulation of TNFR2 synthesis. Macrophages of tmTNFnc mice also produced less TNFR2 than WT macrophages (-30%). Plasmas of tmTNFnc mice contained significantly less sTNFR2 than WT mice (-75%). In conclusion, an increase in tmTNF levels, rather than the lack of sTNF, significantly down-modulated TNFR2 synthesis in aortic endothelial cells, but had no major influence on the synthesis of some major pro-inflammatory and pro-atherothrombotic proteins.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammato... more Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune responses, but its significance in non-infectious diseases remains unclear. Here, we demonstrate that TREM-1 promotes cardiovascular disease by exacerbating atherosclerosis. TREM-1 is expressed in advanced human atheromas and is highly upregulated under dyslipidemic conditions on circulating and on lesion-infiltrating myeloid cells in the Apoe À / À mouse model. TREM-1 strongly contributes to high-fat, high-cholesterol diet (HFCD)-induced monocytosis and synergizes with HFCD serum-derived factors to promote pro-inflammatory cytokine responses and foam cell formation of human monocyte/macrophages. Trem1 À / À Apoe À / À mice exhibit substantially attenuated diet-induced atherogenesis. In particular, our results identify skewed monocyte differentiation and enhanced lipid accumulation as novel mechanisms through which TREM-1 can promote atherosclerosis. Collectively, our findings illustrate that dyslipidemia induces TREM-1 surface expression on myeloid cells and subsequently synergizes with TREM-1 to enhance monopoiesis, pro-atherogenic cytokine production and foam cell formation.

International Immunology, 2002

Acute graft-versus-host disease (GvHD) is a serious complication after allogeneic bone marrow tra... more Acute graft-versus-host disease (GvHD) is a serious complication after allogeneic bone marrow transplantation. Donor-derived T cells in®ltrate recipient target organs and cause severe tissue damage, often leading to death of the affected patient. Tissue destruction is a direct result of donor CD8 + T cell activation and cell-mediated cytotoxicity. IL-18 is a novel pro-in¯ammatory cytokine with potent T h 1 immune response-promoting and cytotoxic T lymphocyte (CTL)-inducing activity. IL-18 is strongly induced in experimental mouse models and human patients with acute GvHD. However, the precise role of IL-18 in the development of acute GvHD is still unknown. In this study, we have used IL-18-binding protein, a soluble IL-18 decoy receptor, to speci®cally neutralize IL-18 in vivo and in vitro. Our results demonstrate that IL-18 is induced during GvHD. However, its effect in the induction of GvHD appears to be redundant, since neutralization of IL-18 does not alter any disease parameter analyzed. Our study further shows that IFN-g production and CTL induction upon activation by T cell mitogens or by alloantigen does not involve IL-18mediated ampli®cation, in contrast to lipopolysaccharide-induced IFN-g production. We conclude that IL-18 expression correlates with the course of GvHD; however, its effect is dispensable for IFN-g and CTL induction for the initiation phase of this disease, most likely due to direct, IL-18independent, CTL activation.