Project acronym AUTO-CD
Project COELIAC DISEASE: UNDERSTANDING HOW A FOREIGN PROTEIN DRIVES AUTOANTIBODY FORMATION
Researcher (PI) Ludvig Magne Sollid
Host Institution (HI) UNIVERSITETET I OSLO
Call Details Advanced Grant (AdG), LS6, ERC-2010-AdG_20100317
Summary The goal of this project is to understand the mechanism of how highly disease specific autoantibodies are generated in response to the exposure to a foreign antigen. IgA autoantibodies reactive with the enzyme transglutaminase 2 (TG2) are typical of coeliac disease (CD). These antibodies are only present in subjects who are HLA-DQ2 or -DQ8, and their production is dependent on dietary gluten exposure. This suggests that CD4+ gluten reactive T cells, which are found in CD patients and which recognise gluten peptides deamidated by TG2 in context of DQ2 or DQ8, are implicated in the generation of these autoantibodies. Many small intestinal IgA+ plasma cells express membrane Ig hence allowing isolation of antigen specific cells. Whereas control subjects lack anti-TG2 IgA+ plasma cells, on average 10% of the plasma cells of CD patients are specific for TG2. We have sorted single TG2 reactive IgA+ plasma cells, cloned their VH and VL genes and expressed recombinant mAbs. So far we have expressed 26 TG2 specific mAbs. There is a strong bias for VH5-51 usage, and surprisingly the antibodies are modestly mutated. TG2 acts on specific glutamine residues and can either crosslink these to other proteins (transamidation) or hydrolyse the glutamine to a glutamate (deamidation). None of the 18 mAbs tested affected either transamidation or deamidation leading us to hypothesise that retained crosslinking ability of TG2 when bound to membrane Ig of B cells is an integral part of the anti-TG2 response. Four models of how activation of TG2 specific B cells is facilitated by TG2 crosslinking and the help of gluten reactive CD4 T cells are proposed. These four models will be extensively tested including doing in vivo assays with a newly generated transgenic anti-TG2 immunoglobulin knock-in mouse model.
Summary
The goal of this project is to understand the mechanism of how highly disease specific autoantibodies are generated in response to the exposure to a foreign antigen. IgA autoantibodies reactive with the enzyme transglutaminase 2 (TG2) are typical of coeliac disease (CD). These antibodies are only present in subjects who are HLA-DQ2 or -DQ8, and their production is dependent on dietary gluten exposure. This suggests that CD4+ gluten reactive T cells, which are found in CD patients and which recognise gluten peptides deamidated by TG2 in context of DQ2 or DQ8, are implicated in the generation of these autoantibodies. Many small intestinal IgA+ plasma cells express membrane Ig hence allowing isolation of antigen specific cells. Whereas control subjects lack anti-TG2 IgA+ plasma cells, on average 10% of the plasma cells of CD patients are specific for TG2. We have sorted single TG2 reactive IgA+ plasma cells, cloned their VH and VL genes and expressed recombinant mAbs. So far we have expressed 26 TG2 specific mAbs. There is a strong bias for VH5-51 usage, and surprisingly the antibodies are modestly mutated. TG2 acts on specific glutamine residues and can either crosslink these to other proteins (transamidation) or hydrolyse the glutamine to a glutamate (deamidation). None of the 18 mAbs tested affected either transamidation or deamidation leading us to hypothesise that retained crosslinking ability of TG2 when bound to membrane Ig of B cells is an integral part of the anti-TG2 response. Four models of how activation of TG2 specific B cells is facilitated by TG2 crosslinking and the help of gluten reactive CD4 T cells are proposed. These four models will be extensively tested including doing in vivo assays with a newly generated transgenic anti-TG2 immunoglobulin knock-in mouse model.
Max ERC Funding
2 291 045 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
Project acronym CLR SENSING NECROSIS
Project Immune Functions of Myeloid Syk-coupled C-type Lectin Receptors Sensing Necrosis
Researcher (PI) David Sancho Madrid
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Summary
Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.
Max ERC Funding
1 297 671 €
Duration
Start date: 2010-12-01, End date: 2016-08-31
Project acronym CMVAGSTIMULUS
Project Molecular mechanisms of persistent antigenic stimulation in cytomegalovirus infection
Researcher (PI) Luka Cicin-Sain
Host Institution (HI) HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Cytomegalovirus (CMV) is a ubiquitous herpesvirus, latently persisting in the majority of the adult population worldwide. In these hosts, CMV-specific memory cells dominate the immune memory compartment. It follows that CMV-specific T-cells dominate the memory compartment of the majority of the human population worldwide.
I propose to define within this project the molecular mechanisms driving the inflation of CMV-specific T-cells. My central hypothesis is that expression levels of CMV peptides during latency, along with the avidity of T-cell receptors for peptide MHC complexes, define the amplitude of T-cell responses. A corollary hypothesis is that vigorous T-cell responses in CMV infection are defined by factors that drive CMV gene expression during latency, such as inflammatory stimuli.
This hypothesis will be verified in a model of in vivo CMV latency and immune monitoring. We will benefit from state-of-the-art inducible genetic systems, where recombinant mouse CMV will be deployed in transgenic mice. In latently infected mice, we will induce or suppress the expression of immunodominant CMV genes, and define downstream effects on T-cell response kinetics. In parallel, we will define the T-cell responses to high and low avidity peptides.
Understanding the mechanisms driving the strong T-cell response to CMV is of outstanding biological and clinical relevance. If strong T-cell responses may be redirected to target heterologous antigens of interest, CMV-based vaccine vectors might potentially allow the development of HIV or tumor vaccines. On the other hand, it is speculated that the control of latent CMV may overcommit the aging immune system and exhaust the T-cell repertoire. Given the CMV pervasiveness, discerning the mechanisms of its T-cell induction may define novel molecular targets for rejuvenation strategies. In either case, the proposed research has groundbreaking potential in the field of infection and immunity.
Summary
Cytomegalovirus (CMV) is a ubiquitous herpesvirus, latently persisting in the majority of the adult population worldwide. In these hosts, CMV-specific memory cells dominate the immune memory compartment. It follows that CMV-specific T-cells dominate the memory compartment of the majority of the human population worldwide.
I propose to define within this project the molecular mechanisms driving the inflation of CMV-specific T-cells. My central hypothesis is that expression levels of CMV peptides during latency, along with the avidity of T-cell receptors for peptide MHC complexes, define the amplitude of T-cell responses. A corollary hypothesis is that vigorous T-cell responses in CMV infection are defined by factors that drive CMV gene expression during latency, such as inflammatory stimuli.
This hypothesis will be verified in a model of in vivo CMV latency and immune monitoring. We will benefit from state-of-the-art inducible genetic systems, where recombinant mouse CMV will be deployed in transgenic mice. In latently infected mice, we will induce or suppress the expression of immunodominant CMV genes, and define downstream effects on T-cell response kinetics. In parallel, we will define the T-cell responses to high and low avidity peptides.
Understanding the mechanisms driving the strong T-cell response to CMV is of outstanding biological and clinical relevance. If strong T-cell responses may be redirected to target heterologous antigens of interest, CMV-based vaccine vectors might potentially allow the development of HIV or tumor vaccines. On the other hand, it is speculated that the control of latent CMV may overcommit the aging immune system and exhaust the T-cell repertoire. Given the CMV pervasiveness, discerning the mechanisms of its T-cell induction may define novel molecular targets for rejuvenation strategies. In either case, the proposed research has groundbreaking potential in the field of infection and immunity.
Max ERC Funding
1 498 456 €
Duration
Start date: 2011-04-01, End date: 2016-09-30
Project acronym CTLANDROS
Project Reactive Oxygen Species in CTL-mediated Cell Death: from Mechanism to Applications
Researcher (PI) Denis Martinvalet
Host Institution (HI) UNIVERSITE DE GENEVE
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells release granzyme and perforin from cytotoxic granules into the immune synapse to induce apoptosis of target cells that are either virus-infected or cancerous. Granzyme A activates a caspase-independent apoptotic pathway and induces mitochondrial damage characterized by superoxide anion production and loss of the mitochondrial transmembrane potential, without disrupting the integrity of the mitochondrial outer membrane; while causing single-stranded DNA damage. GzmB induces both caspase-dependent and caspase-independent cell death. In the caspase-dependent pathway, mitochondrial functions are altered as evidenced by the loss of mitochondrial transmembrane potential and the generation of reactive oxygen species (ROS). The mitochondrial outer membrane (MOM) is disrupted, resulting in the release of apoptogenic factors. To date, research on mitochondrial-dependent apoptosis has focused on mitochondrial outer membrane permeabilization (MOMP) however whether the generation of ROS is incidental or essential to the execution of apoptosis remains unclear. Like human GzmA, human GzmB promotes cell death in a ROS-dependent manner. Preliminary data suggest that human GzmB can induce ROS in a MOMP-independent manner as Bax and Bak double knockout MEF cells treated with human GzmB and perforin still display a robust ROS production and dye in an ROS-dependent manner. Since GzmA and GzmB induce cell death in a ROS-dependent manner, we hypothesize that oxygen free radicals are central to the execution of programmed cell death induced by the cytotoxic granules. Therefore, the goal of this proposal is to dissect the key molecular events triggered by ROS that lead to Citotoxic Tcell-induced target cell death. A combination of biochemical, genetic and proteomic approaches in association with Electron Spin Resonance (ESR) spectroscopy methodology will be used to unravel the essential role ROS play in CTL-mediated killing.
Summary
Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells release granzyme and perforin from cytotoxic granules into the immune synapse to induce apoptosis of target cells that are either virus-infected or cancerous. Granzyme A activates a caspase-independent apoptotic pathway and induces mitochondrial damage characterized by superoxide anion production and loss of the mitochondrial transmembrane potential, without disrupting the integrity of the mitochondrial outer membrane; while causing single-stranded DNA damage. GzmB induces both caspase-dependent and caspase-independent cell death. In the caspase-dependent pathway, mitochondrial functions are altered as evidenced by the loss of mitochondrial transmembrane potential and the generation of reactive oxygen species (ROS). The mitochondrial outer membrane (MOM) is disrupted, resulting in the release of apoptogenic factors. To date, research on mitochondrial-dependent apoptosis has focused on mitochondrial outer membrane permeabilization (MOMP) however whether the generation of ROS is incidental or essential to the execution of apoptosis remains unclear. Like human GzmA, human GzmB promotes cell death in a ROS-dependent manner. Preliminary data suggest that human GzmB can induce ROS in a MOMP-independent manner as Bax and Bak double knockout MEF cells treated with human GzmB and perforin still display a robust ROS production and dye in an ROS-dependent manner. Since GzmA and GzmB induce cell death in a ROS-dependent manner, we hypothesize that oxygen free radicals are central to the execution of programmed cell death induced by the cytotoxic granules. Therefore, the goal of this proposal is to dissect the key molecular events triggered by ROS that lead to Citotoxic Tcell-induced target cell death. A combination of biochemical, genetic and proteomic approaches in association with Electron Spin Resonance (ESR) spectroscopy methodology will be used to unravel the essential role ROS play in CTL-mediated killing.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-05-01, End date: 2016-04-30
Project acronym DCSUBSET
Project Cross-species characterisation of CD8alpha+ dendritic cells and their role in immune regulation
Researcher (PI) Caetano Maria Pacheco Pais Dos Reis E Sousa
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS6, ERC-2010-AdG_20100317
Summary Dendritic cells (DC) are a heterogeneous family of leucocytes with important functions in immunity. Little is known about the role of distinct DC subtypes in vivo. In the mouse, a subset known as CD8alpha+ DC has been argued to represent a discrete DC lineage with specialised properties. These include a superior capacity for presenting exogenous antigens to CD8+ and CD4+ T cells, which makes CD8alpha+ DC an attractive target in vaccination and tolerisation. However, it is unclear whether CD8alpha+ DC fulfill unique and non-redundant roles in the immune system. In addition, the reported restriction of CD8alpha+ DC to thymus and secondary lymphoid organs is hard to reconcile with their documented capacity to act as presenting cells for antigens outside those organs. Finally, CD8alpha+ DC have not been identified in humans, greatly restricting their use in immunotherapy. In this proposal, we exploit the recent finding that DNGR-1 (CLEC9A) acts as a new and specific marker for the CD8alpha+ lineage to address these issues. We will generate DNGR-1-Cre mice as a universal tool to manipulate gene expression in the subset. We will use such mice to render CD8alpha+ DC sensitive to toxic proteins that permit constitutive or transient ablation of the subset for functional studies. DNGR-1-Cre mice will further be used to express fluorescent proteins in CD8alpha+ DC, allowing tracing of the lineage in vivo, both in lymphoid and non-lymphoid organs. Finally, we will use the DNGR-1 marker to identify and characterise putative CD8alpha+ DC equivalents in humans. The results from this proposal will illuminate the function of CD8alpha+ DC across species and open the door for using this intriguing DC subset in immunotherapy of cancer, infectious and autoimmune diseases.
Summary
Dendritic cells (DC) are a heterogeneous family of leucocytes with important functions in immunity. Little is known about the role of distinct DC subtypes in vivo. In the mouse, a subset known as CD8alpha+ DC has been argued to represent a discrete DC lineage with specialised properties. These include a superior capacity for presenting exogenous antigens to CD8+ and CD4+ T cells, which makes CD8alpha+ DC an attractive target in vaccination and tolerisation. However, it is unclear whether CD8alpha+ DC fulfill unique and non-redundant roles in the immune system. In addition, the reported restriction of CD8alpha+ DC to thymus and secondary lymphoid organs is hard to reconcile with their documented capacity to act as presenting cells for antigens outside those organs. Finally, CD8alpha+ DC have not been identified in humans, greatly restricting their use in immunotherapy. In this proposal, we exploit the recent finding that DNGR-1 (CLEC9A) acts as a new and specific marker for the CD8alpha+ lineage to address these issues. We will generate DNGR-1-Cre mice as a universal tool to manipulate gene expression in the subset. We will use such mice to render CD8alpha+ DC sensitive to toxic proteins that permit constitutive or transient ablation of the subset for functional studies. DNGR-1-Cre mice will further be used to express fluorescent proteins in CD8alpha+ DC, allowing tracing of the lineage in vivo, both in lymphoid and non-lymphoid organs. Finally, we will use the DNGR-1 marker to identify and characterise putative CD8alpha+ DC equivalents in humans. The results from this proposal will illuminate the function of CD8alpha+ DC across species and open the door for using this intriguing DC subset in immunotherapy of cancer, infectious and autoimmune diseases.
Max ERC Funding
2 499 998 €
Duration
Start date: 2011-09-01, End date: 2017-08-31
Project acronym ERSTRESS
Project Role of Endoplasmic Reticulum Stress in dendritic cells and immune-mediated lung diseases
Researcher (PI) Bart Lambrecht
Host Institution (HI) UNIVERSITEIT GENT
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary My overall aim is to understand the physiologic and medical importance of lung dendritic cells (DC) and to define the suitability of inhibitors of their function for the treatment of inflammatory lung diseases like asthma and COPD.
Lung dendritic cells (DC) play crucial roles in the regulation of lung immunity. We still do not fully understand how they get activated in response to different types of environmental triggers like allergens, cigarette smoke and pathogens. Although recognition of conserved motifs by pattern recognition receptors on DCs could be a key event, these stimuli are also accompanied by accumulation of unfolded proteins in the endoplasmic reticulum (ER). Cells respond by mounting the unfolded protein response (UPR) that acts to ameliorate protein folding, but intersects with metabolism, induction of alarm signals and cellular suicide mechanisms. I hypothesize that the presence of unfolded proteins and ER stress in DCs is a crucial endogenous danger signal that is vital to understanding their biology and their involvement in inflammatory lung diseases.
My specific aims are to :
1.define the fine tuning of ER stress pathways in various lung DC subsets in health and disease
2. define the specific role of ER stress proteins XBP1, JIK and ORMDL3 in DCs
3. test if interfering with ER stress pathways alters the course of inflammatory lung disease
To approach these aims, I have developed mouse models of lung disease that are centered around lung DCs and where ER stress pathways can be genetically deleted. Using a combination of cell biological and immunological techniques I hope to achieve definitive answers as to how ER stress pathways regulate the function of DCs. Manipulation of ER stress pathways by drugs will have a major impact on very common diseases like diabetes, cardiovascular and neurodegenerative disease. Through the current proposal, I hope to extend this exciting field to lung biology.
Summary
My overall aim is to understand the physiologic and medical importance of lung dendritic cells (DC) and to define the suitability of inhibitors of their function for the treatment of inflammatory lung diseases like asthma and COPD.
Lung dendritic cells (DC) play crucial roles in the regulation of lung immunity. We still do not fully understand how they get activated in response to different types of environmental triggers like allergens, cigarette smoke and pathogens. Although recognition of conserved motifs by pattern recognition receptors on DCs could be a key event, these stimuli are also accompanied by accumulation of unfolded proteins in the endoplasmic reticulum (ER). Cells respond by mounting the unfolded protein response (UPR) that acts to ameliorate protein folding, but intersects with metabolism, induction of alarm signals and cellular suicide mechanisms. I hypothesize that the presence of unfolded proteins and ER stress in DCs is a crucial endogenous danger signal that is vital to understanding their biology and their involvement in inflammatory lung diseases.
My specific aims are to :
1.define the fine tuning of ER stress pathways in various lung DC subsets in health and disease
2. define the specific role of ER stress proteins XBP1, JIK and ORMDL3 in DCs
3. test if interfering with ER stress pathways alters the course of inflammatory lung disease
To approach these aims, I have developed mouse models of lung disease that are centered around lung DCs and where ER stress pathways can be genetically deleted. Using a combination of cell biological and immunological techniques I hope to achieve definitive answers as to how ER stress pathways regulate the function of DCs. Manipulation of ER stress pathways by drugs will have a major impact on very common diseases like diabetes, cardiovascular and neurodegenerative disease. Through the current proposal, I hope to extend this exciting field to lung biology.
Max ERC Funding
1 499 580 €
Duration
Start date: 2010-12-01, End date: 2015-11-30
Project acronym EXPLORE
Project Exploring novel pathways governing immunity and leukemia by studying the genetic basis of human myeloid cell defects - from genetics to gene therapy
Researcher (PI) Christoph Klein
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Advanced Grant (AdG), LS6, ERC-2010-AdG_20100317
Summary Genomic system biology approaches offer new aspects to understand the basis of diseases and to develop new therapeutic strategies. Here, we propose to study rare human variants of the immune system to provide novel explanations of mechanisms governing inflammation and leukemogenesis. Following a full circle of translational research, our group has previously defined several novel clinical entities and elucidated their molecular defects (Nat Med 2007, NEJM 2009). Further studies have highlighted the critical role of new pathways for general biological principles (Immunity 2005, Nat Gen 2007, Nat Med 2008). Finally, we have developed innovative gene and cell-based therapeutic strategies and tested their feasibility in clinical trials (JCO 2007, NEJM2009).
The overall goal of ¿Explore¿ is to decipher novel pathways controlling myeloid cell function and leukemogenesis. The following specific aims are proposed:
1. To elucidate genetic defects causing neutrophil disorders in children by homozygosity mapping and to perform functional studies in vitro and in vivo using relevant animal models
2. To identify novel genes controlling endoplasmic reticulum cell function and the secretory pathway in myeloid cells by employing RNA-interference technology
3. To define the role of novel factors involved in controlling the topology of the endoplasmic reticulum and ER-stress in murine model systems
4. To study the role of HAX1 in hematopoisis and leukemogenesis using a new murine HAX1flox allele and to develop a clinical gene therapy approach for patients with severe congenital neutropenia due to HAX1-deficiency
These studies will not only identify novel genetic factors controlling human immunity and leukemogenesis, but may ultimately impact on the development of novel therapeutic strategies.
Summary
Genomic system biology approaches offer new aspects to understand the basis of diseases and to develop new therapeutic strategies. Here, we propose to study rare human variants of the immune system to provide novel explanations of mechanisms governing inflammation and leukemogenesis. Following a full circle of translational research, our group has previously defined several novel clinical entities and elucidated their molecular defects (Nat Med 2007, NEJM 2009). Further studies have highlighted the critical role of new pathways for general biological principles (Immunity 2005, Nat Gen 2007, Nat Med 2008). Finally, we have developed innovative gene and cell-based therapeutic strategies and tested their feasibility in clinical trials (JCO 2007, NEJM2009).
The overall goal of ¿Explore¿ is to decipher novel pathways controlling myeloid cell function and leukemogenesis. The following specific aims are proposed:
1. To elucidate genetic defects causing neutrophil disorders in children by homozygosity mapping and to perform functional studies in vitro and in vivo using relevant animal models
2. To identify novel genes controlling endoplasmic reticulum cell function and the secretory pathway in myeloid cells by employing RNA-interference technology
3. To define the role of novel factors involved in controlling the topology of the endoplasmic reticulum and ER-stress in murine model systems
4. To study the role of HAX1 in hematopoisis and leukemogenesis using a new murine HAX1flox allele and to develop a clinical gene therapy approach for patients with severe congenital neutropenia due to HAX1-deficiency
These studies will not only identify novel genetic factors controlling human immunity and leukemogenesis, but may ultimately impact on the development of novel therapeutic strategies.
Max ERC Funding
2 496 648 €
Duration
Start date: 2012-01-01, End date: 2017-06-30
Project acronym IMMEMO
Project Protective and pathogenic immunological memory and its organisation by stroma cells
Researcher (PI) Andreas Radbruch
Host Institution (HI) Deutsches Rheuma-Forschungszentrum Berlin
Call Details Advanced Grant (AdG), LS6, ERC-2010-AdG_20100317
Summary "Immunological memory provides immunity against recurrent pathogens, but also can induce and regulate immunopathology. In chronic immune-mediated diseases, a ""pathogenic"" immunological memory probably is the essential driver of inflammation, refractory to physiological regulation and state-of-the-art therapeutic immunosuppression, and thus a challenge for the development of novel, curative therapeutic strategies. Despite its relevance, immunological memory is poorly understood. We recently discovered memory plasma cells and professional memory T helper cells, and their organisation by bone marrow stroma and the stroma of inflamed tissues. We have identified genes and regulating function and persistence of memory and effector cells in the resting state and in chronic immune reactions. Based on these intriguing, paradigm-breaking initial results, I propose to develop and lead a research program addressing the organisation and role of immunological memory in protective immunity and in immune-mediated diseases, on the systemic, cellular and molecular level. In particular, I propose to (1) analyse the homing of plasmablasts and T helper memory cell precursors to dedicated survival niches of the bone marrow or inflamed tissues, (2) identify the niches of CD8 memory cells and memory B cells, (3) analyse the cellular and molecular composition of memory niches, (4) decipher the molecular communication between stromal cells and immune memory cells, (5) analyse how memory/effector T helper cells are reactivated, (6) define the role of memory-phenotype T cells in the periphery, (7) analyse the role of twist1 and hop for persistence and function of pathogenic Th memory/effector cells, and (8) develop strategies to selectively delete pathogenic immune memory cells."
Summary
"Immunological memory provides immunity against recurrent pathogens, but also can induce and regulate immunopathology. In chronic immune-mediated diseases, a ""pathogenic"" immunological memory probably is the essential driver of inflammation, refractory to physiological regulation and state-of-the-art therapeutic immunosuppression, and thus a challenge for the development of novel, curative therapeutic strategies. Despite its relevance, immunological memory is poorly understood. We recently discovered memory plasma cells and professional memory T helper cells, and their organisation by bone marrow stroma and the stroma of inflamed tissues. We have identified genes and regulating function and persistence of memory and effector cells in the resting state and in chronic immune reactions. Based on these intriguing, paradigm-breaking initial results, I propose to develop and lead a research program addressing the organisation and role of immunological memory in protective immunity and in immune-mediated diseases, on the systemic, cellular and molecular level. In particular, I propose to (1) analyse the homing of plasmablasts and T helper memory cell precursors to dedicated survival niches of the bone marrow or inflamed tissues, (2) identify the niches of CD8 memory cells and memory B cells, (3) analyse the cellular and molecular composition of memory niches, (4) decipher the molecular communication between stromal cells and immune memory cells, (5) analyse how memory/effector T helper cells are reactivated, (6) define the role of memory-phenotype T cells in the periphery, (7) analyse the role of twist1 and hop for persistence and function of pathogenic Th memory/effector cells, and (8) develop strategies to selectively delete pathogenic immune memory cells."
Max ERC Funding
2 465 000 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym IMMUNO
Project Immunogenomics: Mouse to Human Translational Research
Researcher (PI) Adrian Liston
Host Institution (HI) VIB VZW
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Control over the activation of the immune system is central to the key issues of human health. Autoimmunity, atopy, persistent infections and tumours all share a common root cause in a sub-optimal balance between immune activity and tolerance. At the heart of this balance are T cells, with the capacity for both activation and suppression. Research in mouse models has allowed enormous progress to be made on understanding fundamental mechanics, and yet the next step translating this understanding into therapeutics has proven far more difficult than originally anticipated. The basis of this problem may be a reliance on the mouse model without parallel human research. In this project we propose to create a dynamic interplay between the technological advantages of working in mouse models and the physiological relevance of studying the human immune system in three key research areas.
The first research track is a gene discovery program, using an immunology-orientated approach to allow the discovery of important human disease genes that remain invisible to clinically-orientated approaches. The second research track is a functional genomics program, seeking to address the mechanistic questions that arise from traditional disease-gene association studies. This information is of critical importance in translating genetic data into therapeutic interventions and provides the basis for personalised medicine. The third research track is a direct hypothesis-driven project testing the role that genetic variation in the target organ alters susceptibility to autoimmune disease. Each of these research tracks utilises cutting edge technology in genetics and immunology, combining knowledge from mouse models with innovative study design in human populations.
Summary
Control over the activation of the immune system is central to the key issues of human health. Autoimmunity, atopy, persistent infections and tumours all share a common root cause in a sub-optimal balance between immune activity and tolerance. At the heart of this balance are T cells, with the capacity for both activation and suppression. Research in mouse models has allowed enormous progress to be made on understanding fundamental mechanics, and yet the next step translating this understanding into therapeutics has proven far more difficult than originally anticipated. The basis of this problem may be a reliance on the mouse model without parallel human research. In this project we propose to create a dynamic interplay between the technological advantages of working in mouse models and the physiological relevance of studying the human immune system in three key research areas.
The first research track is a gene discovery program, using an immunology-orientated approach to allow the discovery of important human disease genes that remain invisible to clinically-orientated approaches. The second research track is a functional genomics program, seeking to address the mechanistic questions that arise from traditional disease-gene association studies. This information is of critical importance in translating genetic data into therapeutic interventions and provides the basis for personalised medicine. The third research track is a direct hypothesis-driven project testing the role that genetic variation in the target organ alters susceptibility to autoimmune disease. Each of these research tracks utilises cutting edge technology in genetics and immunology, combining knowledge from mouse models with innovative study design in human populations.
Max ERC Funding
1 496 688 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym INTRACELLTB
Project A Chemical Genomics Approach of
Intracellular Mycobacterium tuberculosis
Towards Defining Specific Host Pathogen Interactions
Researcher (PI) Priscille Marie Monique Brodin
Host Institution (HI) INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Call Details Starting Grant (StG), LS6, ERC-2010-StG_20091118
Summary Tuberculosis, caused by Mycobacterium tuberculosis is still a major threat to global health. Because the treatment of an infected individual requires more than six months of chemotherapy, compliance is low, which can result in the development of multidrug resistant (MDR-TB) strains. New drugs and new targets are needed to combat MDR-TB. A critical feature of the Mycobacterium tuberculosis bacillus is its ability to survive and even replicate within macrophages, making these host cells an ideal niche for persisting microbes. The goal of our project is to understand the biological mechanisms underlying the persistence of intracellular mycobacteria and to develop novel approaches to eradicate the bacillus from its hiding spot. To this end, we have been undertaking global approaches using visual phenotypic assays (relying on monitoring by automated confocal fluorescence microscopy) of the trafficking and replication of M. tuberculosis inside macrophages. Screening of a small interfering RNA library, a M. tuberculosis transposon mutant library and hundreds of thousands of small chemical molecules has led to the identification of key host and mycobacterial genes involved in the intracellular fate of M. tuberculosis, as well as chemicals able to prevent intracellular bacterial growth. Building on the considerable data generated and on the powerful high throughput / high content (HT/HC) confocal microscopy, our project is to further explore the signalling pathways used specifically by M. tuberculosis. We will focus on the in depth study of bacterial protein effectors belonging to the ESX and PPE families and of the SOCS family member CISH, which promotes intracellular mycobacterial survival. Finally, chemicals that target cellular partners of M. tuberculosis will constitute a new starting point for the development of drugs able to counteract this host response manipulation without directly targeting the pathogen, thereby overcoming the issue of the emergence of MDR-TB.
Summary
Tuberculosis, caused by Mycobacterium tuberculosis is still a major threat to global health. Because the treatment of an infected individual requires more than six months of chemotherapy, compliance is low, which can result in the development of multidrug resistant (MDR-TB) strains. New drugs and new targets are needed to combat MDR-TB. A critical feature of the Mycobacterium tuberculosis bacillus is its ability to survive and even replicate within macrophages, making these host cells an ideal niche for persisting microbes. The goal of our project is to understand the biological mechanisms underlying the persistence of intracellular mycobacteria and to develop novel approaches to eradicate the bacillus from its hiding spot. To this end, we have been undertaking global approaches using visual phenotypic assays (relying on monitoring by automated confocal fluorescence microscopy) of the trafficking and replication of M. tuberculosis inside macrophages. Screening of a small interfering RNA library, a M. tuberculosis transposon mutant library and hundreds of thousands of small chemical molecules has led to the identification of key host and mycobacterial genes involved in the intracellular fate of M. tuberculosis, as well as chemicals able to prevent intracellular bacterial growth. Building on the considerable data generated and on the powerful high throughput / high content (HT/HC) confocal microscopy, our project is to further explore the signalling pathways used specifically by M. tuberculosis. We will focus on the in depth study of bacterial protein effectors belonging to the ESX and PPE families and of the SOCS family member CISH, which promotes intracellular mycobacterial survival. Finally, chemicals that target cellular partners of M. tuberculosis will constitute a new starting point for the development of drugs able to counteract this host response manipulation without directly targeting the pathogen, thereby overcoming the issue of the emergence of MDR-TB.
Max ERC Funding
1 982 371 €
Duration
Start date: 2010-12-01, End date: 2015-11-30
