PhD Fellows and their research projects

Research area: Hematopoiesis and Development



Paola Fernanda Ruiz Aparicio

University Medical Center Freiburg

Department of Rheumatology and Clinical Immunology

 

Contact ✉

A dysregulated B cell compartment and formation of auto-reactive plasma cells (PC) are important drivers of antibody-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE). In SLE, plasma cells may play a direct role in the pathogenesis of lupus nephritis due to the production of pathogenic antibodies. In addition, plasma cells may confer therapy resistance as they persist in specific niches, such as bone marrow or inflamed kidneys of lupus mice and patients. Thus, the development of strategies to selectively eliminate such pathogenic PC requires a thorough understanding of their biology and crosstalk within survival niches, which is still poorly understood. The aim of this project is to characterize stroma cells as well as accessory cells in such functional units. Furthermore, we will explore how cellular and molecular niche components impact recruitment, activation, and differentiation of B cells into plasma cells as well as their survival and function. Our questions will be addressed in vivo employing murine lupus models as well as primary human cells from patients with autoimmune diseases.

 

Supervisor: Prof. Dr. Reinhard Voll

Co-supervisor: Dr. Christopher Mueller (University of Strasbourg)


Guillermo Federico Perez

University of Strasbourg

Institute of Molecular and Cell Biology

 

Contact ✉

Human stromal cells have recently been recognized as mediators of long term inflammation in most chronic diseases, and as such, could be more effective therapeutic targets than short-lived cells like some hematopoietic cells. In this project we want to elucidate proinflammatory mechanisms of these cells, especially in relation with its immune microenvironment and find possible ways to revert this process.My PhD project will focus on vaccine induced remodeling of the lung macrophage compartment in mice and humans. The goal is to understand how mucosal versus intradermal delivery of BCG (the only available vaccine for tuberculosis) impacts lung macrophage heterogeneity and function.

 

Supervisor: Dr. Christopher Mueller

Co-supervisor: Prof. Dr. Reinhard Voll


Annia Pérez Riverón

University of Strasbourg

Institute of Molecular and Cell Biology

 

Contact ✉

The nasal mucosa, including the olfactory epithelium, constitutes an infection site for SARS-CoV-2 virus. Damage to olfactory neurons, caused by the virus or the antiviral response, may lead to anosmia. Olfactory neurons could also represent a portal for viral invasion of the central nervous system. However, the precise mechanisms by which SARS-CoV-2 impairs olfactory function remain unclear. Based on our know-how of tissue-engineered skin, we propose to construct in vitro a human 3D model of innervated and immunocompetent olfactory mucosa. This model will be used to investigate how SARS-CoV-2 may harm the olfactory epithelium, how the immune network protects this environment and whether topical application of an antiviral glycolipidic compound patented by our team (Mannovirocide) could prevent infection.

 

Supervisor: Dr. Vincent Flacher

Co-supervisor: Prof. Dr. Hartmut Hengel (University Medical Center Freiburg)


Agnibesh Dey

University Medical Center Freiburg

Institute for Immunodeficiency, CCI

 

Contact ✉

Cytomegalovirus (CMV), a β-herpesvirus, has a long history of existing or rather co-existing with mammals. Human CMV (HCMV) infects humans in the first few months, and enter the host system either through intestine or respiratory track and establishes themselves within the host. The resulting infection causes a lifelong persistence with alternating between latent and active infection stage. It is still being investigated upon the defined immune response towards primary infection. To understand such mechanism mouse CMV (MCMV) models have been established because of their remarkable similarities with HCMV and thus to study the CMV biology.
My project is to investigate macrophage populations regarding CMV infection. Newborn mice mimic an early human second trimester foetus in terms of neurodevelopment. Post infection of mice with MCMV I investigate the central neuron system (CNS) macrophages that includes microglia and border associated macrophages (BAMs). Microglia are prominent populations in brain and are considered to be the first line of defence regarding inflammation or infection in brain. This allows me to understand the host defence mechanism regarding the first wave of active infection and eventually establish a better treatment for the disease

 

Supervisor: Prof. Dr. Philipp Henneke


Mahassen El Khoury

University of Strasbourg, IGBMC

Project: Role of the Ikaros family proteins in embryonic blood cell development

 

Contact ✉

Hematopoiesis is controlled by many regulatory networks, including a series of specific transcription factors. The Ikaros family proteins are zinc finger transcription factors, comprising Ikaros, Aiolos, Helios, Eos and Pegasus. These proteins participate in a complex network of interactions to regulate important cell-fate decisions during hematopoiesis. Definitive hematopoiesis first begins in the Aorta-Gonad-Mesonephros region of the embryo where Hematopoietic Stem Cells (HSCs) emerge from a subset of specialized endothelial cells, named Hemogenic Endothelium, via a process known as the Endothelial-to-Hematopoietic Transition. Although the expression and role of the Ikaros family are relatively well studied in adult hematopoiesis as both activators and repressors of gene expression; much less is known about their expression and implication during embryogenesis and HSC emergence. My project seeks to understand the implication of the Ikaros family proteins in the establishment of the hematopoietic system during embryonic development.

Supervisor: Dr. Susan Chan

Co-supervisor: Dr. Peggy Kirstetter (University of Strasbourg)


Research area: Innate and adaptive effector functions


Gabriel Rojas Jiménez

University of Strasbourg

EFS Grand Est

 

Contact ✉

Platelet alloimmunization and the associated refractory state remain a serious adverse transfusion event. The project focuses on the role of splenic cellular subpopulations in the alloimmune response. It also encompasses the interactions between transfused platelets and the recipient's splenic microenvironment, and how these regulate platelet alloimmune response and transfusion efficiency.

 

Supervisor: Dr. Blandine Maitre

 


Danielle Paige Anthony

University Medical Center Freiburg

Institute for Medical Microbiology and Hygiene

 

Contact ✉

Inflammasomes are essential components of the innate immune system that function when stimulated to induce inflammation through processing of IL-1β. This study is focused on the post translational modifications (Ubiquitylation, glutathionylation) of IL-1β and their impact on its secretion and processing by Inflammasomes. Previous work has shown that IL-1β ubiquitylation can be driven by reactive oxygen species (ROS) derived from mitochondria. Mitochondrial Metabolism has also been implicated in Inflammasome signalling pathways. Therefore, we also intend to explore the mechanism of mitochondrial ROS generation and how it regulates il-1b ubiquitylation.

 

Supervisor:  Prof. Dr. Georg Häcker

Co-supervisor: Dr. Romeo Ricci (University of Strasbourg)


Vasileios Morfos

University of Freiburg

Institute of Biology III

 

Contact

Most current checkpoint immunotherapies target inhibitory receptors on T-cells to improve anti-tumor responses. These treatments only amplify and prolong existing anti-tumor responses. This contributes to low response rates in patients. Therefore, we will attempt to elicit additional T-cell responses against weak tumor antigens by reducing  activation thresholds of the T-cell receptor pathway. We hypothesize that detrimental side effects (e.g. cytokine storms and auto-immunity) can be avoided by targeting Zap70 kinase, which will preserve antigen specificity and inherent feedback loops. Specifically, we will utilize two Zap70 mutants with the propensity to remain in an open conformation. In preliminary studies, these mutants have shown prolonged T-cell receptor binding and consequently increased T-cell activity. We will test if these mutants improve anti-tumor immunity in mouse colon adenocarcinoma models alone or in combination with traditional checkpoint inhibitors. If successful, their molecular characteristics will be exploited to develop novel allosteric activators for the treatment of cancer.

 

Supervisor: Prof. Dr.  Björn Lillemeier

Co-supervisor: Prof. Dr. Susana Minguet (University of Freiburg)


Bruno Benassini

University Medical Center Freiburg

Rheumatology and Clinical Immunology

 

Contact ✉

ANCA associated vasculitis (AAV) are autoimmune diseases characterised by the presence of autoantibodies. The presence of autoantibodies and the clinical response to B cell depletion point to a role for B cells in disease pathogenesis and perpetuation. Our group identified perturbances of the B cell compartment in AAV patients. In this project we will study the origins of the break of tolerance in the B cell compartment resulting in autoantibody formation and the role of self reactive B cells in disease maintenance. The project will take advantage of the established AAV cohort hosted in the Vasculitis Center at the Department of Rheumatology and Clinical Immunology at the University Medical Center in Freiburg.

 

Supervisor:  Prof. Dr. Marta Rizzi

Co-supervisor: Dr. Anne-Sophie Korganow (University of Strasbourg)


Xipeng Wang

University Medical Center Freiburg

Institute of Neuropathology

 

Contact ✉

The NLRP3 inflammasome is crucial in innate immunity, regulating IL-1β and IL-18 secretion and inducing pyroptosis via Gasdermin D cleavage. It's implicated in various cancers and is notably overexpressed and hyperactivated in acute myeloid leukemia (AML), where it promotes disease progression through IL-1β. Additionally, oncogenic KRAS can enhance this pro-inflammatory pathway. The study hypothesizes that certain oncogenes can activate the NLRP3
inflammasome.


The research aims to identify which oncogenes trigger NLRP3 activation and to elucidate the molecular mechanisms involved. Initially, it will use expression data from AML patient databases to identify these oncogenes and pathways. Then, it will validate their effects on NLRP3 activation in primary cells and cell lines, exploring the specific pathways involved. The study will also use genetically modified mouse models to investigate these mechanisms in vivo, potentially uncovering new cancer therapy targets.

 

Supervisor: Prof. Dr. Olaf Groß, Institut für Neuropathologie-Uniklinik Freiburg.


Cemre Seven

University of Basel

Department of Biomedicine

 

Contact ✉

Persistent viral diseases continue to represent a significant burden to public health. The  lymphocytic chronomeningitis virus (LCMV) infection model in mice has been extensively used to characterise adaptive immune defense during chronic viral infection. While the role of cellular immunity has been worked out in much detail, mechanisms of humoral immunity during chronic viral infection remains comparably poorly defined. We and others have shown that neutralising antibody responses are required for the clearance of protracted LCMV in mice. Interestingly, we have also found that chronic viral infection in mice leads to potent germinal center B cell responses and highly hypermutated antibodies. Hence, in this study, we aim to characterise how the chronic infection leads to but possibly also hampers the process of B cell receptor affinity maturation. We plan to infect mice with engineered LCMV variants, followed by the adoptive transfer of receptor-engineered virus-specific B cells. We will also engineer a range of LCMV nAb variants mimicking the evolutionary trajectory of a single nAb ancestor, and test their affinities against the LCMV surface glycoprotein using biolayer interferometry. We expect the  knowledge gained from this work should give directions to vaccination strategies aimed at mimicking or improving B cell responses against chronic viruses.

 

Supervisor: Prof. Dr. Daniel Pinschewer

Co-supervisor: Prof. Dr. Stephan Ehl (University Medical Center Freiburg)


Clara Dufossez

University Medical Center Freiburg

Institute of Neuropathology

 

Contact ✉

The NLRP3 inflammasome is an important component of innate immunity. It controls maturation and secretion of the leaderless pro-inflammatory cytokines IL-1β and IL-18 as well as the cleavage of Gasdermin D, leading to a lytic, pro-inflammatory type of cell death called pyroptosis. The precise molecular mechanisms of NLRP3 activation are still poorly understood. The aim of this project is to better understand the effect of different molecules on NLRP3 inflammasome activation and its function in macrophages using in vitro and in vivo techniques.

 

Supervisor: Prof. Dr. Olaf Groß

Co-supervisor: Dr. Romeo Ricci (University of Strasbourg)


Shadrack Owusu

University of Strasbourg

Institue of Molecular and Cell Biology

 

Contact ✉

Lymph nodes are specialized secondary lymphoid organs essential for initiating adaptive immunity. They provide an environment in which antigen-specific lymphocytes can optimally interact with antigen-presenting dendritic cells (DCs) and macrophages. Our lab has shown that the interaction of the receptor activator of NF-kappaB (RANK) expressed by lymphatic endothelial cells (LECs) with its ligand RANKL is vital for differentiating macrophages in lymph nodes. Moreover, LECs produce chemokines that recruit DCs from peripheral organs (i.e. the skin) to the lymph nodes. Studies about the phenotypic and functional heterogeneity of LEC subpopulations have revealed that LECs residing in the subcapsular sinus of lymph nodes have an unanticipated function in immune cell entry.
Altogether, we hypothesize that genetic deletions targeted at LECs may impact the migration of DCs to the lymph nodes, affect the activation of T cells and alter the immune response.
Therefore, we wish to study whether and how the disruption of RANK-RANKL may impair immune cell trafficking in the lymph nodes under steady and inflamed states. Knowledge gained from this project could be important to advance current immunotherapies targeted to autoimmune diseases and cancer.

 

Supervisor: Dr. Christopher Mueller

Co-supervisor: Prof. Dr. Alfred Zippelius (University of Basel)


Vanshika Rastogi

University of Basel

Clarunis - Universitäres Bauchzentrum Basel

 

Contact ✉

IBD (Inflammatory Bowel Disease) is an idiopathic chronic relapsing and remitting inflammatory conditions of the intestine encompassing two types of clinical disorders: Crohn’s Disease characterised by transmural inflammation in segments of the digestive track and ulcerative colitis which involves inflammation and ulcers along the superficial lining of colon and rectum. This chronic inflammation is attributed to a dysregulated immune response towards antigens or metabolic products of gut microbiota.

Our aim is to assess the role of an unconventional T cell subset called MR1-restricted T cells. MR1-restricted T cells are a novel population which show a high degree of αβTCR diversity. They are autoreactive towards MR1 and can recognise MR1-expressing tumor cell lines as well as stressed epithelial cells. In this project we would investigate the presence and frequency of these MR1-restricted T cells along with other subsets of T cells like MAITs and γ/δ cells in the inflamed and non-inflamed regions of the gut from the patients of IBD. We aim to phenotypically and functionally characterise MR1-restricted T cells in healthy and diseased gut tissues to assess their role

 

Supervisor: Prof. Dr. Petr Hruz

Co-supervisor: Prof. Dr. Peter Hasselblatt (University Medical Center Freiburg)

 


Natalie Kehrer

University of Basel

 

 

Contact ✉

 

 

Supervisor: Prof. Dr. Gennaro De Libero

Co-supervisor: Prof. Dr. Wolfgang Schamel (Univeristy of Freiburg)


Research area: Immune-related diseases



Trang Nguyen

University of Freiburg

Department of Immunology

 

Contact ✉

The T cell receptor (TCR) is a protein complex locates on the surface of T cells that is responsible for recognizing antigen as peptides bound to major histocompatibility complex (MHC) molecules. The aim of my project is to engineer new TCRs by fusing a single-chain variable (scFv) fragment of a solid anti-tumour antigen antibody to one of the TCR sub-units. This will allow the TCRs to recognize the tumor antigen in a MHC-independent manner, and reprogram T cells to kill tumor cells. In addition, an off-switch will be introduced in order to shut off the T cell response in case of on-target off-tumor cytotoxicity. The new structure will be tested in vitro and in pre-clinical mouse models.

 

Supervisor: Prof. Dr. Wolfgang Schamel

Co-supervisor: Prof. Dr. Gennaro De Libero (University of Basel)


Irene Fusi

University of Basel

Tumour Immunology

 

Contact ✉

Cancer immunotherapy has revolutionized cancer therapy. In particular, immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-(L)1 demonstrated potent and durable anti-tumor efficacy. Still, the majority of patients do not benefit from ICIs, while many others, who initially respond, later develop disease progression. Therefore, it is of the utmost importance to understand the mechanisms underlying therapy resistance.

The aim of my project is to understand the mechanisms of resistance to anti-PD-1/CTLA-4 combination therapy. To this end, we developed a bilateral syngeneic, orthotopic breast cancer model that results in a fraction of animals who initially respond to the therapy, others who do not respond, and those that relapse after initially responding. Moreover, the introduction of a second contra-lateral tumor allows us to study the tumor microenvironment (TME) at an early timepoint of response or resistance and follow the fate of the second tumor in the opposite flank of the mice. By doing this, we will obtain a longitudinal study of the tumor response after checkpoint blockade, which allows us to address mechanisms behind ICI resistance.

To obtain a comprehensive view of the immune infiltrate inside the TME in responding and non-responding/relapsing mice we will perform single-cell RNA sequencing and 5’UTR VDJ sequencing on intratumoral CD45+ cells, combined with multiplexed imaging.

 

Supervisor: Prof. Dr. Alfred Zippelius

Co-supervisor: Prof. Dr. Lukas Jeker (University of Basel)


Nagwa Ibrahim

Karlsruhe Institute of Technology

IBCS-FMS

 

Contact ✉

The CD44 transmembrane glycoprotein family members, particularly the CD44v6 isoform, have been shown to promote tumor growth and metastasis in different types of cancer including pancreatic ductal adenocarcinoma (PDAC). However, CD44 isoforms are not only expressed on cancer cells but also in the stroma, which makes up to 90% of the PDAC tumor volume. PDAC stromal cells include cancer-associated fibroblasts (CAF), pancreatic stellate cells (PSC), and immune cells including tumor-associated macrophages (TAMs). It has long been established that TAMs are one of the most abundant immune cell types in the tumor microenvironment (TME), and that they exhibit different phenotypes ranging from the classically activated M1 phenotype which favors inflammation to the alternatively activated phenotype which is anti-inflammatory and pro-tumoral. Since CD44 isoforms are involved in the progression of PDACs and are expressed on macrophages, the aim of this project is to investigate its potential role in the polarization of macrophages from the anti-tumor M1 phenotype to the pro-tumor M2 phenotype using the Cd44 knockout (KO) mouse models: Cd44fl/fl;Csfr1Cre and/or Cd44fl/fl;Csfr1CreERT2. Using the same mouse models, we also aim at exploring the consequences of a Cd44 KO on macrophages on tumor growth and metastasis. Finally, an interaction between CD44-expressing TAMs and other components of the TME such as the extracellular matrix (ECM) will be investigated. Such potential role of CD44 on TAMs can reveal a new mechanism by which the TAMs promote PDAC tumor growth and hence will lead to the possible development of targeted therapies against PDAC.

 

Supervisor:  Prof. Dr. Véronique Orian-Rousseau

Co-supervisor: Dr. Gertraud Orend (University of Strasbourg)


Alina Makeeva

University of Basel

Allergy & Immunity

 

Contact ✉

Mastocytosis is a heterogeneous disease defined by aberrant tissue mast cell proliferation and accumulation in various organs, most frequently bone marrow and skin. This project aims to study signaling pathways in systemic mastocytosis (SM) in ex vivo mouse models and in human cell lines. This task is of utmost importance as current treatment options for patients with SM are often not sufficient, especially for the subgroup of patients with advanced forms of SM that have a very poor prognosis. The most common molecular alteration in SM is an activating mutation in the KIT gene, KITD816V in humans (or KitD814V in mice), carried by more than 80% of patients.
In this project, novel KitD814Vflox mouse lines will be generated and characterized. Then, the different downstream signaling pathways that may be activated or affected by activation of the KIT receptor will be investigated in mouse models and in human mastocytosis cell lines. Also, the potential impact the KitD814V mutation on MC function will be examined ex vivo and treatments with known TKI and inhibitors of select pathways will be performed. Finally, select findings will be confirmed in human MC isolated from mastocytosis patients.

 

Supervisor: Prof. Dr. Karin Hartmann

Co-supervisor: Prof. Stephan Ehl (University Medical Center Freiburg)


Victoria Cousin

University Medical Center Freiburg

CCI - ZTZ

 

Contact ✉

Our lab is interested in the pathomechanisms underlying the immunodeficiency and autoimmunity in common variable immunodeficiency (CVID). The aim of this project is to explore non-hematopoietic stromal niches in secondary lymphoid organs (SLO), especially of the disturbed germinal center (GC), which are crucial for the generation of high-affinity long lasting humoral immune responses.
Therefore, we will visualize the niches required to allow for proper GC and plasma cell formation in SLO of patients with disturbed GC function compared to SLO of immunocompetent donors. Here we will utilize multiepitope ligand microscopy (MELC) for multidimensional immunohistochemistry. In addition, we aim to deep-phenotype protein and transcripts of lymphoid stromal cells by flow-cytometric and RNAseq experiments in comparison to previous data from immunocompetent donors. Finally, we will develop and perform functional assays for stromal cell- B cell interaction by in-vitro co-cultures. By the combination of these three approaches we will shed not only light on the disturbed function of lymphoid stroma in CVID, but will potentially discover new essential interactions between the immune system and the niche-forming stroma.

 

Supervisor: Prof. Dr. Klaus Warnatz

Co-supervisor: Dr. Christopher Mueller (University of Strasbourg)

 


Wadschma Naderi

University of Basel

Department of Biomedicine

 

Contact ✉

 

 

Supervisor: Prof. Dr. Carolyn King

 


Wasihun Hailemichael

University Medical Center Freiburg

Internal Medicine II

 

Contact ✉

Hepatitis B virus (HBV) infection is a major global health burden with over 300 million chronically infected people worldwide and causes life-threatening liver disease. Adaptive Immunity particularly CD8+ T cells are pivotal in determining the outcome of infection.  In chronic HBV infection, virus-specific CD8+ T cells are functionally impaired. Previous data from our group demonstrated that the thymocyte selection-associated high mobility group box protein TOX is linked to functional adaptation and the degree of dysfunction of HBV-specific CD8+ T cells in different clinical phases of infection (Heim et.al, Gut 2020). TOX expression in HBV-specific CD8+ T cells is also affected by the targeted antigens (HBV core versus HBV polymerase). This observation highlights distinct functional adaptation and degrees of dysfunction of virus-specific CD8+ T cells targeting different antigens. In my project, I will investigate the underlying mechanisms of these functional adaptations including the TOX-associated pathways of HBV-specific CD8+ T cells targeting different antigens dependent on the clinical phase. These analyses will inform immuno-therapeutic approaches, which can modulate or restore impaired HBV-specific CD8+ T cells to ultimately achieve HBV cure.

 

Supervisor: Prof. Dr. Robert Thimme & Dr. Maike Hofmann

Co-supervisor: Prof. Dr. Daniel Pinschewer (University of Basel)

Mentor: Dr. Souphlane Luangsay (Roche, Basel, Switzerland)


Haneen Daralnakhla

University Medical Center Freiburg

Institute of Virology

 

Contact ✉

The immune system usually elicits a long-term IgG antibody memory response against viral infections. Despite that, human cytomegalovirus (HCMV) establishes a lifelong infection with recurrent episodes of virus production and shedding. This can be due to the sophisticated immune evasion strategies developed over millions of years of co-evolution with the human host. These strategies include the expression of antagonists to the host Fc-gamma receptors (FcγR), preventing different types of immune cells from executing the needed immune response. Examples of these antagonists are the viral Fc-gamma-binding glycoproteins (vFcγRs) gp34/RL11, gp68/UL119-118 and gp95/RL12. Our laboratory has demonstrated the manipulation of IgG memory B cells’ function after binding of vFcγR gp34, which prevents plasma blast formation and antibody production. Moreover, gp34 modulates non-IgG+ B cells by triggering the release of TNF-α via IgG+ B cells, which prevents plasma blast formation of non-IgG B cells and the release of IgA and IgM. 

In this project, we aim to optimize the production of gp34 and gp68, in order to determine the ultrastructures of (i) the individual molecules gp34 and gp68, (ii) in complex with their respective ligands and (iii) when interacting in parallel we. Ultrastructure determination helps gaining a better understanding of their molecular interactions and three-dimensional structures in conjunction with their target assemblies.

 

Supervisor: Prof. Dr. Hartmut Hengel

Co-supervisor: Prof. Dr. Tobias Derfuss (UNiversity of Basel)

Mentor: Prof. Dr. Carola Hunte (University of Freiburg)