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IRTG: Integrated Research Training Group SFB 685  / Alumni

Scholarship holder: Olaf-Oliver Wolz (PhD)
Associated Member: Olaf-Oliver Wolz (PhD)

Name:

Olaf-Oliver Wolz (PhD)

Project:

Supervisor:

Alexander N. Weber

Email

o.wolz(@)student.uni-tuebingen.de

Scholarship:

01.04.2012 - 31.03.2013

Associated:

01.04.2013 - 30.06.2016

Abstract:

Characterization and therapeutic targeting of MyD88 and Interleukin-1 receptor associated kinases (IRAKs) in lymphoma and leukemia

Diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue lymphoma (MALT) and chronic lymphocytic leukemia (CLL) are associated with considerable mortality. Recent whole-genome sequencing showed 29% of ABC DLBCL, 9% of MALT lymphomas and 5.6% of a subtype of CLL harbor a gain-of-function mutation in the gene MYD88, Leu 265 Pro (L265P), which is thought to sustain tumor cell proliferation via activation of the transcription factor NF-κB. MyD88 is a pivotal adaptor protein in Toll-like receptor, Interleukin-1 receptor and TACI-receptor signaling. MyD88 signals in cooperation with Interleukin-1 receptor-associated kinases (IRAKs) via an oligomeric protein complex termed the Myddosome. IRAK inhibition may be a therapeutic option in MyD88 L265P-positive malignancies, where Myddosome complexes are thought to be constitutively assembled. On the other hand, being tumor-specific, the MyD88 mutation L265P may represent a target for peptide-based T-cell-mediated immunotherapy, provided that L265P peptides are presented on tumor cells. Since most studies of IRAK have been done in mice, many aspects of IRAK and Myddosome function in human cells remain unclear, precluding a safe and specific therapeutic exploitation of the MyD88-IRAK axis. To address this problem we propose the following approaches: 1) Structural and molecular properties of human MyD88 and IRAKs and the influence of MyD88 mutation and IRAK inhibition on signaling events. 2) Myddosome properties and the impact of IRAK inhibition will be assessed in DLBCL and CLL cell lines as well as primary DLBCL and CLL cells from patients.
Together, these studies may provide valuable insights and concrete therapeutic options applicable for the therapy of DLBCL, CLL as well as other diseases in which MyD88/IRAK signaling has been implicated.


Scholarship holder: Max Wiedenmann (MD)

Name:

Max Wiedenmann (MD)

Project:

C03

Supervisor:

Peter Lang / Patrick Schlegel

Email

Opens window for sending emailmaximilian.wiedenmann(@)student.uni-tuebingen.de

Scholarship:

01.04.2015 - 30.09.2015

Associated:

01.10.2015 - 31.07.2016

Abstract:

Impact of inhibitory, activatory and KIR RL signaling on NK cell mediated ADCC using the FC-optimized CD19 antibody 4G7SDIE

Killer immunoglobulin-like receptors (KIRs) is a group of polymorphic inhibitory and activatory surface receptors specific for allelic forms of human leukocyte antigen (HLA) class I molecules. KIRs are expressed by natural killer (NK) cells and subsets of T lymphocytes. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. Cells lacking HLA class I molecules are promptly killed by NK cells because of the predominant effect of several activating NK receptors [1]. The interaction of killer immunoglobulin-like receptor HLA I has been shown absolutely relevant for the survival of patients suffering from leukemia [2, 3]. In adults this was demonstrated only for acute myeloid leukemia (AML) [2], whereas in children it was proven to have a significant impact on AML and acute lymphoblastic leukemia (ALL) [4]. In this project we will carve out the effect of KIR RL match vs mismatch, the impact of further inhibitory and activatory signaling (NKG2a, NKG2D, DNAM-1) on native, cytokine activated as well as expanded NK cells on the Fc-optimized anti-CD19 mAb 4G7SDIE mediated ADCC in CD19 positive ALL in the context of haploidentical hematopoietic stem cell transplantation.

 

1. Moretta, L. and A. Moretta, Killer immunoglobulin-like receptors. Curr Opin Immunol, 2004. 16(5): p. 626-33.

2. Cooley, S., et al., Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood, 2010. 116(14): p. 2411-9.

3. Cooley, S., et al., Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. J Immunol, 2014. 192(10): p. 4592-600.

4. Oevermann, L., et al., KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood, 2014. 124(17): p. 2744-7.


Associated Member: Desirée Syring (MD)

Name:

Desirée Syring

Project:

C03

Supervisor:

Peter Lang

Email:

Status:

MD-student

Associated:

01.03.2015 - 31.07.2016

Abstract:

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MD scholarship holder: Jonas Schmidt

Name:

Jonas Schmidt

Project:

A07

Supervisor:

Helmut Salih

Email

Opens window for sending emailJonas.Schmidt(@)student.uni-tuebingen.de

Scholarship:

01.03.2015 - 31.08.2015

Associated:

01.09.2015 - 31.07.2016

Abstract:

Neutralization of B cell activating factor (BAFF) to enhance the susceptibility of chronic lymphocytic leukemia to systemic treatment.

B cell activating factor (BAFF) is a type II transmembrane protein of the TNF superfamily, is mainly expressed on cells of the myeloid lineage and acts either as a membrane-bound or as a soluble factor. BAFF influences the development, differentiation, proliferation and survival of B cells as well as production of immunoglobins. Said effects are mediated by three different receptors: BAFF-receptor (BAFF-R), transmembrane activator-calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation protein (BCMA). Until recently, BAFF has mainly been investigated for its involvement in autoimmune diseases like systemic lupus erythematosus (SLE). Neutralizing of BAFF by the monoclonal antibody Belimumab (Benlysta®) in order to reduce BAFF-induced proliferation and antibody production was approved for treatment of SLE in 2011. Furthermore, BAFF was shown to be involved in the pathophysiology of B cell malignancies like chronic lymphoid leukemia (CLL), where it promotes cell survival, decreases the efficacy of chemotherapy and inhibites apoptosis. Our project aims to enhance the susceptibility of CLL cells to small molecules like Ibrutinib, Idelalisib and Abt-199 by using the BAFF-neutralizing antibody Belimumab. The overall goal is to evaluate whether Belimumab can serve to improve treatment options of CLL.


MD scholarship holder: Lukas Osburg (MD)

Name:

Lukas Osburg (MD)

Project:

C14

Supervisor:

Gundram Jung, Hans-Georg Rammensee

Email

Opens window for sending emaillukas.osburg(@)student.uni-tuebingen.de

Scholarship:

01.08.2015 - 31.01.2016

Associated:

01.02.2016 - 31.07.2016

Abstract:

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Associated Member: Alexander Jöchner (MD)

Name:

Alexander Jöchner (MD)

Project:

C03

Supervisor:

Peter Lang

Email:

Opens window for sending emailalex_joechner(@)web.de

Status:

MD-student

Associated:

01.03.2015 -  30.06.2016

Abstract:

NK cell and  γδ T cell alloreactivity in neuroblastoma, impact of activating and inhibitory signalling on direct cytotoxicity and ADCC

The ongoing study NCT02258815 has shown favorable survival of relapsed stage IV neuroblastoma by intensification of treatment via haploidentical hematopoietic stem cell transplantation and subsequent anti-GD2 immunotherapy. Donor selection by KIR-genotyping has been shown to dramatically determine event-free survival in AML and pediatric ALL. The impact on survival in neuroblastoma remains unclear. Nevertheless, the genetic background of the KIR genes alone does not define the NK alloreactive potential of donors. Many other genes are involved in regulating the NK cell activity. Therefore, functional donor assessment needs implementation for donor selection strategies as well as the immune characterization of the primary tumor and metastasis that will profile the tumor and will help to estimate the susceptibility for immune recognition.


Associated Member: Michael Buch (PhD)

Name:

Michael Buch (PhD)

Project:

B03

Supervisor:

Thilo Stehle

Email:

michaelbuch(@)gmx.net

Status:

PhD-student

Associated:

01.04.2011 - 30.06.2016

Abstract:

Structural and Functional Analysis of Murine Polyomavirus Capsid Proteins Provide Insights into Ligand Recognition and Pathogenicity

Murine Polyomavirus (MuPyV) is a small dsDNA virus with a T=7d icosahedral capsid. Like most of the members of the family Polyomaviridae, it utilizes gangliosides to gain entrance to the host cell [1]. It has been shown in the past that singular amino acid exchanges in the receptor binding pocket of the major capsid protein, VP1, can lead to strikingly different behavior regarding pathogenicity and tissue tropism. While a low pathogenicity strain (LP) bears a glycine residue at position 91, a medium pathogenicity strain (MP) carries a glutamate residue at this position, and a high pathogenicity strain (HP) shows an additional V296A mutation [2, 3]. 

It was previously thought that MP and HP are unable to bind branched chain oligosaccharide moieties of various gangliosides, and therefore can be much more specific during host cell exit and spread from cell to cell. Contrarily, LP was suspected to be capable of binding a wide spectrum of pseudoreceptors that not only prevent effective infection but also hamper viral spread within the host upon cell egression [4].

Our recent investigations into the VP1 structures of these three MuPyV strains demonstrate that, surprisingly, all three strains are capable of binding straight and branched-chain oligosaccharides. By analyzing the binding affinities of all three strains to representative oligosaccharides occurring in the three main pathways of ganglioside biosynthesis we have gained insight into the different pathogenicity profiles on an atomic level. 

 

1. Tsai B, Gilbert JM, Stehle T, Lencer W, Benjamin TL, and Rapoport TA, Gangliosides are receptors for murine polyoma virus and SV40. EMBO J, 2003. 22(17): p. 4346-55.

2. Bauer PH, Cui C, Liu WR, Stehle T, Harrison SC, DeCaprio JA, and Benjamin TL, Discrimination between sialic acid-containing receptors and pseudoreceptors regulates polyomavirus spread in the mouse. J Virol, 1999. 73(7): p. 5826-32.

3. Freund R, Calderone A, Dawe CJ, and Benjamin TL, Polyomavirus tumor induction in mice: effects of polymorphisms of VP1 and large T antigen. Journal of virology, 1991. 65(1): p. 335-41.

4. Stehle T and Harrison SC, Crystal structures of murine polyomavirus in complex with straight-chain and branched-chain sialyloligosaccharide receptor fragments. Structure, 1996. 4(2): p. 183-94.


Associated Member: Marlene Ballbach (PhD)

Name:

Marlene Ballbach (PhD)

Project:

Supervisor:

Dominik Hartl

Email

Opens window for sending emailmarlene.ballbach(@)med.uni-tuebingen.de

Status:

PhD student

Associated:

15.10.2013 - 31.07.2016

Abstract:

Role of sterile and chitin-mediated inflammation in myeloid-derived suppressor cell (MDSC) homeostasis

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population of myeloid origin. They expand during pathological conditions (cancer, infection) and show a distinct combination of surface markers. Through their capacity to suppress T-cell activity via ROS, iNOS or arginase, MDSCs are considered to be key players in the balance between innate and adaptive immune responses, especially under chronic disease conditions. While the role of MDSCs in cancer and bacterial infection has been studied, their role in sterile and fungal inflammation remains poorly understood. This projects focuses on the mechanisms and receptors by which sterile (inflammasome-driven) and chitin (fungal-driven) pro-inflammatory signals modulate MDSCs, by combining human cell culture, siRNA knock-down and murine models. Modulation of MDSCs may serve as a novel therapeutic approach for the treatment of auto-inflammatory and fungal diseases.

 


Associated Member: Nicole Janssen

Name:

Nicole Janssen

Project:

Center of Medical Research, Eberhard Karls University

Supervisor:

Graham Pawelec

Email:

Opens window for sending emailnicijanssen(@)googlemail.com

Status:

PhD-student

Associated:

01.08.2014 - 30.04.2016

Abstract:

The percentage of old individuals in our society is increasing as life expectancy increases. Older age is the major risk for solid cancers and the incidence and prevalence of most cancers increases with age. Thus, it is reasonable to ask whether there is not only an association between cancer development and chronological ageing but “immunological” ageing as well. There are several reports on age-associated changes of adaptive immune cells, but much less is known about how ageing affects cells of the innate immune system. Not only chronological ageing causes “immunological” ageing, but also chronic antigenic stress can result in premature immunosenescence, which is already described in persistent viral infections. The tumour itself is also a persistent antigen source and thus immune cells of cancer patients are constantly exposed. Thus, this chronic antigenic stress could result in premature immunosenescence as well. Therefore, we want to investigate immune profiles of the immune system in cancer patients to examine whether cancer induces premature immunosenescence. In addition we want to analyze whether this could be used as a predictive immune profile for “healthy aging” and “morbidity” in a longitudinal study on aged individuals.


Associated Member: Aline Lindner (MD)

Name:

Aline Lindner

Project:

C03

Supervisor:

Peter Lang

Email:

Status:

MD-student

Associated:

01.10.2015 - 31.03.2016

Abstract:

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Associated Member: Anne Schilling

Name:

Anne Schilling

Project:

C03

Supervisor:

Peter Lang, Patrick Schlegel

Email

Opens window for sending emailAnne.Schilling(@)stundent.uni-tuebingen.de

Status:

MD-Student

Associated:

01.04.2014 - 31.03.2016

Abstract:

Impact of γδ T cells on NK cell mediated lysis of B-precursor leukemia after TcRαβ/CD19 depleted haploidentical hematopoietic stem cell transplantation (HSCT)

Relapse is still the major cause of death in high-risk and refractory pediatric ALL patients. Alternative donor HSCT using haploidentical donors has been established in 1995 starting with CD34+ enrichment of stem cells, moving on to CD3/CD19 depletion. Recently we have started a trial using TcRαβ/CD19 depletion instead of CD3/CD19 depletion. The TcRαβ/CD19 trial is aimed to show a benefit of effector cell recovery compared to previous graft manipulation methods in terms of prevention of infections and reduction of relapse. In TcRαβ/CD19 depletion T cell recovery, especially that of γδ T cells is significantly faster than in CD34+ and CD3/CD19 depleted transplantation. In this medical thesis we focus on γδ T cell mediated lysis of leukemic blasts and their impact on NK cell mediated lysis of B-precursor leukemia after haploidentical TcRαβ/CD19 depleted HSCT.


PhD scholarship holder: Patrick Günther
Associated Member: Patrick Günther

Name:

Patrick Günther
(
Organisation Internat. Symposium: "Moving forward in Immunology" Oct. 2012)

Project:

C06

Supervisor:

Gerhard Jahn

Email

patrick.günther@med.uni-tuebingen.de

Scholarship:

01.04.2011 - 31.03.2012

Associated:

01.04.2012 - 31.03.2016

Abstract:

Human adenoviruses are known to induce mild and self-limiting infections of the respiratory tract in immuno-competent individuals. However infections of immuno-compromised patients, especially children after stem cell transplantation, cause high morbidity and mortality. Hence, identification of HLA-class I-restricted peptide epitopes from clinical adenovirus isolates could lead to improved treatment strategies for those patients.
We have previously shown that DC-SIGN (dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin) can function as a receptor for clinically relevant adenovirus species C serotype 2 isolates in the presence of bovine lactoferrin. Therefore, we plan to establish cell lines ectopically expressing DC-SIGN, as an adenovirus receptor, and common HLA-class I molecules. Infection of these cell lines with clinical adenovirus isolates should allow us to obtain a sufficient amount of HLA-class I molecules loaded with adenoviral peptides by immuno-precipitation. We aim to identify the isolated adenoviral peptides by mass spectrometry to determine clinically-relevant adenovirus epitopes presented by defined HLA class I molecules. These epitopes could be helpful in the development of a peptide vaccine or to improve the selection of adenovirus-specific T lymphocytes for adoptive transfer in order to treat adenoviral infections in immuno-compromised patients.


Associated Member: Stefanie Souczek

Name:

Stefanie Souczek

Project:

DKTK (German Cancer Consortium)

Supervisor:

Stefan Stevanović

Email

Opens window for sending emailstefanie.souczek(@)gmx.de

Associated:

01.10.2012 - 29.02.2016

Abstract

Immunogenicity of TUMAPs identified in prostate cancer

Prostate cancer is the second most common cancer diagnosed among men and is the sixth most common cause of cancer death among men. In a recent phase I/II immunotherapy study using 11 HLA-A*02 restricted synthetic peptides in 37 HLA-A*02+ prostate carcinoma patients a vaccine-induced immune response in almost all patients could be shown. Recently our group identified about 50 additional prostate specific peptides presented by HLA-A*01, -A*03, -A*11, -A*68, or HLA-B*07, -B*27, -B*44, -B*47, -B*49, -B*51, -B*57. Together with HLA-A*02 these HLA types cover essentially the entire population. 

The aim of this study is to test the identified peptides for immunogenicity with the final aim to develop a multipeptide vaccination cocktail consisting of about 20 HLA class I peptides. The immunogenicity testing is done by priming of CD8+ T cells from healthy blood donors with artificial antigen presenting cells (aAPCs). These aAPCs are synthetic beads which are coated with MHC class I/peptide complexes and anti-CD28 as costimulatory signal. The PBMCs or enriched T cells are stimulated three times with the loaded beads in weekly intervals. For additional stimulation the cytokines IL-2 and IL-12 are added to the T-cell medium. Peptide-specific CD8+- T cells will be identified by FACS analysis after tetramer staining. In our first experiments two B*07 restricted peptides were able to induce specific T-cell responses after aAPC priming.

 


Associated Member: Kilian Wistuba-Hamprecht

Name:

Kilian Wistuba-Hamprecht

Project:

from the Graduate Center of the Medical Faculty (School of Immunology)

Supervisor:

Graham Pawelec

Email:

Opens window for sending emailkilian.wistuba-hamprecht(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.11.2012 - 29.02.2016

Abstract:

"Human gd T-Cells in aging"

γδ T-cells are a small population of non-MHC-restricted lymphocytes which share characteristics of both innate and adaptive immune cells. The antigens recognized by γδ receptors remain mostly unknown, but it has been shown recently that they recognize small phosphorylated molecules as well as stress-induced surface proteins in tissues. The focus of my thesis is the investigation of age and age-related effects on human γδ T-cells. One major factor strongly influencing age-associated changes of the human immune system is a latent infection with Cytomegalovirus (CMV). Despite the common perception that life-long CMV infection is usually asymptomatic, emerging epidemiological evidence suggests that it may in fact be associated with higher mortality. Mechanisms responsible for this potentially important effect are unclear. CMV infection is known to have a large impact on the distribution of T cell phenotypes, especially the accumulation of late-stage differentiated CD8pos, as well as Vδ2negγδ T-cells, which are the main subset of γδ T-cells involved in anti-CMV immunity. Its impact on γδ T-cells in the aging context is less well-defined and is a major aspect of my thesis.
.......


PhD scholarship holder: Julia Wild
Associated Member: Julia Wild

Name:

Julia Wild

Project:

A07

Supervisor:

Helmut R. Salih

Email

wild.julia85(@)googlemail.de

Scholarship:

01.04.2011 - 31.03.2012

Associated:

01.04.2012 - 31.10.2015

Abstract:

The success of monoclonal antibodies (mAb) in anti-tumor therapy like Rituximab for B cell lymphoma has been attributed to several particularities including their ability to activate Fc receptor IIIa (FcγRIIIa, CD16). The latter is expressed on innate immune effector cells like natural killer (NK) cells and induces antibody-dependent cellular cytotoxicity (ADCC) and cytokine release. NK cells are cytotoxic lymphocytes and play an important role in tumor immune surveillance, especially of leukemia. Their reactivity is governed by various activating and inhibitory molecules expressed by their targets including multiple members of the TNF (tumor necrosis factor) family. The TNF super family comprises a variety of molecules which are critically involved in cell proliferation, differentiation and apoptosis. The TNF family member B cell activating factor (BAFF) is expressed on the surface of various cell types and can also be released in a soluble form by shedding from the cell surface. BAFF binds to three different receptor molecules that are mainly expressed on B lymphocytes: transmembrane activator and CAML interactor (TACI), B cell maturation protein (BCMA) and BAFF receptor (BAFF-R). The interaction of BAFF with its receptors contributes to the development, differentiation, proliferation and survival of B cells. Interestingly, expression of BAFF was not detected in healthy B cells but in malignant cells of B cell origin like chronic lymphocytic leukemia (CLL) and protects tumor cells from apoptosis and enhances survival. Dysregulated expression of BAFF was also shown to be involved in autoimmune diseases like systemic lupus erythematosus (SLE). Neutralization of BAFF by the monoclonal antibody Belimumab (Benlysta®), a mAb for BAFF with a human IgG1 tail, was recently approved for treatment of SLE. It was shown to reduce detrimentally increased B cell proliferation and secretion of autoantibodies by neutralization of BAFF and inhibition of receptor activation in B cells. The effects of Belimumab on NK cell reactivity and its ability to target malignant cells for ADCC by NK cells are yet unknown. This project aims to further investigate the role of BAFF and its receptors in leukemia and the potential benefit of Belimumab for tumor immunotherapy of B cell malignancies


PhD scholarship holder: Lea Prokop, spokesperson students
Associated Member: Lea Prokop, spokesperson students

Name:

Lea Prokop

Project:

C05

Supervisor:

Stefan Stevanović

Email

lea.prokop(@)googlemail.com

Scholarship:

01.04.2012 - 31.03.2013

Associated:

01.04.2013 - 31.10.2015

Abstract

High throughput in vitro priming of tumor specific T cells

Peptide-based cancer vaccines are one promising strategy for immunotherapy against cancer. Our group has characterized large numbers of HLA ligands from tumor cells; among them many that might be used for in vivo induction of tumor-specific immune responses. For the development of peptide-based immunotherapies such peptides should be able to induce in vivo tumor-directed immune responses, especially by CD8+ T cells that have a key role in inducing death of tumor cells. The aim of our work is to establish a fast and efficient workflow to induce tumor-reactive T cells which is based on immunogenicity testing of tumor-extracted HLA ligands. T cells usually depend on professional antigen presenting cells such as autologous dendritic cells (DCs) for specific induction and expansion. Since the generation of dendritic cells is expensive and time consuming with varying quality and amount of differentiated DCs, we established an artificial system to replace cell-based in vitro priming of T cells: streptavidin-coated artificial antigen presenting cells loaded with defined amounts of recombinant HLA molecules and costimulatory antibodies such as anti-CD28 and anti-CD137 (4-1BB). Employing artificial APCs without the need for autologous DCs will lead to successful in vitro priming of tumor-reactive T cells that might provide an indication for novel peptides for immunotherapy.


Associated Member: Nico Trautwein

Name:

Nico Trautwein

Project:

C05

Supervisor:

Stefan Stevanović

Email:

Opens window for sending emailTrautwein.N(@)googlemail.com

Status:

PhD-student

Associated:

01.07.2013 - 31.10.2015

Scholarship:

Abstract:

xxx

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Associated Member: Ursula Seidel, spokesperson students

Name:

Ursula Seidel

Project:

C03

Supervisor:

Peter Lang

Email:

ursula.seidel(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2012 - 31.10.2015

Abstract:

Optimization of NK cell mediated antibody-dependent cellular cytotoxicity (ADCC) in treatment of paediatric B cell leukemia patients with minimal residual disease (MRD)

Allogeneic stem cell transplantation is one of the major therapeutic options in paediatric patients with refractory B cell leukemia. Despite significant improvement of bone marrow and PBSC transplantation over the last decade relapse is still the major cause of death post-transplant due to minimal residual disease (MRD). In order to prevent relapse in patients post-transplant at high risk, long-term immunotherapy using an anti-CD19 antibody for antibody-dependent cellular cytotoxicity purpose (ADCC) is a promising approach which is deployed in one of our ongoing studies. However, effectiveness of antibody treatment highly relies on cytotoxic function of NK cells as key mediators of ADCC. Therefore, the focus of my project is to monitor pharmacokinetic and –dynamic of the antibody applied and thereby optimize antibody treatment in terms of dosage and application interval. Furthermore, antileukemic effects mediated by NK cells in response to the antibody as well as changes on effector cell level will be monitored. Beyond that, strategies to improve effector cell function including clinically available drugs, stem cell donor selection and NK cell engineering will be addressed.


Associated Member: Heiko Schuster

Name:

Heiko Schuster

Project:

C05

Supervisor:

Stefan Stevanović

Email:

heiko_schuster(@)gmx.de

Status:

PhD-student

Associated:

01.04.2011 - 31.10.2015

Abstract:

Identification of new tumor specific HLA-Ligands from isolated tumor cells and cancer stem cells

Renal cell carcinoma and ovarian cancer are both characterized by poor prognosis and high mortality due to late diagnosis and high resistance to conventional chemo- and radiotherapy. Curative treatment for both cancers is often only possible through surgical resection at an early non-metastatic stage.
Looking for new and effective therapeutic options a lot of effort has been put into the development of a specific immunotherapy, aiming at the in vivo induction of a tumor-directed immune response. Our group is especially interested in the identification of tumor specific MHC ligands that can be used for the development of a multivalent peptide vaccine targeting different tumor types. We use HLA Affinity chromatography to isolate HLA molecules from human tumor tissues and identify HLA bound peptides by liquid chromatography coupled mass spectrometry. In order to improve the identification of tumor specific HLA-Ligands we have started to use enzymatic digestion of fresh tumor tissue samples and are performing magnetic or fluorescence based cell sorting to preenrich for tumor cells thereby taking into account the heterogeneous composition of tumor tissues.
In recent years it has become evident that at least some cancers contain a rare population of cancer stem cells (CSC) or tumor initiating cells (TICs) that seem to be ultimately responsible for initiation and growth of cancers as well as frequent relapse of disease after chemo- and radiotherapy. Our aim is to isolate CSCs from different tumor entities and to expand them ex vivo to sufficient numbers while maintaining their stem cell state in order to perform HLA-Ligand extraction and analysis. Thereby we hope to also identifiy HLA-Ligands specific for CSCs.


Associated Member: Janet Peper

Name:

Janet Peper
(
Organisation Internat. Symposium: "Moving forward in Immunology" Oct. 2012)

Project:

C05

Supervisor:

Stefan Stevanović

Email:

janet-peper(@)gmx.de

Status:

PhD-student

Associated:

01.04.2011 - 31.10.2015

Abstract:

Natural HLA-ligands provide novel T-cell antigens for immunotherapy of ovarian carcinoma

Late diagnosis and resistance to chemotherapy are the main reasons for the high mortality among women suffering from ovarian carcinoma (OvCa). New strategies to circumvent this drug resistance are urgently needed. One approach is to develop immunotherapies, including peptide-based cancer vaccines which should induce tumor-specific T cells. Several OvCa-associated antigens have already been identified by expression profiling. Further knowledge regarding MHC-presented peptides derived from tumour-associated antigens is needed for triggering specific T-cell responses.
The purpose of this study is to develop a multivalent peptide-vaccine targeting OvCas.
To identify suitable peptides for vaccination, we first analysed MHC class I ligands of OvCa samples by liquid chromatography coupled mass-spectrometry. Peptides from established tumour-associated antigens (TAA) and peptides from proteins which might be involved in tumourigenesis or angiogenesis were finally selected for in vitro priming of CD8-positive T cells from healthy blood donors. T cells were isolated of PBMCs (peripheral blood mononuclear cells) by magnetic activated cell sorting and stimulated with peptide-pulsed autologous dendritic cells and B-cells.
Up to now we found a HLA-A*0201 restricted peptide derived from HDAC1 (histone deacetylase 1), an estabilshed TAA which is associated with poor prognosis. Several substances targeting HDACs are already in clinical trials. In vitro priming of healthy PBMCs induced T-cell responses against the HDAC1 peptide in six of eleven donors, measured by IFNγ intracellular staining. Those primed T cells also expressed CD107a, TNFα, IL-2 and MIP-1β. In addition, HDAC1-primed T cells lysed peptide-loaded as well as unloaded HLA-A*02 tumour cells, shown by chromium release assay while HLA-A*02 negative cells weren’t lysed. Up to now, this natural HLA-ligand has already been identified on one additional OvCa, three renal cell carcinomas, one breast cancer and on HeLa-cells. Moreover this peptide is also a natural HLA-A*02 ligand of HDAC2, allowing the simultaneously targeting of two different HDACs associated with tumorigenesis.
Furthermore, we identified a HLA-B*3501 restricted peptide derived from HLA-B associated transcript 3 (BAT3), which controls different apoptosis-pathways. T cells targeting this peptide produced INFγ and expressed CD107a and MIP-1β. Additionally, those T cells lysed peptide-loaded, but also unloaded, HLA-B*35 expressing tumour cells. The peptide was also found on five renal cell carcinomas and on acute myeloid leukemia cells.
Our data so far supports the conclusion that these two novel identified T-cell epitopes should be included in pepitde-based vaccination trials.


Associated Member: Mathias Walzer (PhD)

Name:

Mathias Walzer

Project:

B01

Supervisor:

Oliver Kohlbacher

Email:

walzer(@)informatik.uni-tuebingen.de

Status:

PhD-student

Associated:

01.03.2012 -  31.03.2015

Abstract:

Application and development of computational methods for rapid selection of individualized tumor vaccines from genomics, proteomics and ligandomics data

The advent of faster technologies and their extended availability for acquiring data about the genomics, proteomics and ligandomics of a specific cancer patient bring individualized cancer specific immunotherapy in the reach of clinical application.
These technologies include next generation sequencing of DNA and RNA to identify potential cancer specific mutations that will show on protein level and tandem mass spectrometry to identify HLA-ligands on tumor tissue that qualify as a target of vaccination. The detection of novel tumor specific ligands is the first level on a way to a successful cancer immunotherapeutic. The next level is optimal selection of target combination for maximal therapeutic impact. With more tumor specific ligands found this problem is getting more complex and will benefit from algorithmic improvements on target selection.
It is the combination of these technologies that allows for more sensitive, accurate and detailed data analysis to find these low abundant HLA-ligands that can make the difference in cancer immunotherapy.
The integration, combination and analysis of these huge amounts of data to result in therapy relevant information in a tight clinical time frame call for novel and powerful computational methods for cancer specific immunotherapy.


Associated Member: Anurag Singh

Name:

Anurag Singh

Project:

A14

Supervisor:

Dominik Hartl

Email:

Opens window for sending emailanurag807(@)gmail.com

Status:

PhD-student

Associated:

01.07.2013 - 31.07.2015

Abstract:

The cancer microenvironment induces immunosuppressive cells to escape T and NK cell defenses. Importantly, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are induced, but the initial mechanisms and cellular pathways that trigger the generation of these cells are poorly understood. Our research group investigates innate immunosuppressive cell types (MDSCs). Anurag Singh studies the effect of pattern recognition on MDSC induction to adapt principles from infection, where MDSCs accumulate, to targeted cancer immunotherapy. Anurag Singh particularly focuses on fungal infections, as (i) they are common in cancer patients and (ii) potently induce MDSCs. In contrast to bacteria and viruses, fungi expose chitin and are bound by chitinase-like proteins, which are abundantly found in several forms of cancer. This study aims to dissect the interaction of MDSCs, fungi and chitinase-like proteins in vitro and in vivo in order to understand how MDSCs are regulated and can be targeted therapeutically.


MD scholarship holder: Lena Schneider
Associate member: Lena Schneider

Name:

Lena Schneider

Project:

C14

Supervisor:

Annette Staebler, Hans-Georg Rammensee

Email:

Opens window for sending emailLena.schneider(@)htp-tel.de

Status:

MD-student

Scholarship:

01.05.2014 - 31.10.2014

Associated:

01.11.2014 -28.02.2015

Abstract:

Analysis of antigen specific regulatory T-cells (T-Regs) in patients with ovarian cancer

Ovarian cancer is a gynaecological cancers associated with the highest mortality. Due to the insufficient early detection methods and unspecific symptoms, 75% of the patients are diagnosed with stage III or IV disease. Approximately three out of four patients develop recurrence after optimal therapy including radical surgical and cytotoxic therapy. This is due to the primary or acquired chemotherapy resistance against platinum containing regimens, which are the current standard in ovarian cancer therapy. Therefore new therapies with a better outcome and less side effects are urgently needed.

We are currently working on the development of a multi-peptide vaccine for patients with ovarian cancer with a pretreatment of cyclophosphamide for depletion of Regulatory T cells (T-Regs). It is known, that this specialized subgroup of T-helper cells both interacting with self-tolerance and regulation of the immune system. They play an important role in the prevention of autoimmune diseases and also in the development, persistence and progress of malignant diseases. It is also known that T-Regs are found in an increased number in patients with ovarian cancer in a later stage, which is linked to a worse prognosis. Aditionally, it has been shown, that antigen specific T-Regs can also suppress a sufficient T-cell response (Bonertz et al, 2009)

So far, in our group a lot of promising HLA class I and II tumor associated peptides for the planned vaccination trial have been discovered. But their possible influence on inducing antigen specific T-Regs and therefore weaken or avert an sufficient immune response in vaccinated ovarian cancer patients is not clear. 

In this study we would like to identify and analyse antigen specific regulatory T-cells in venous and bone marrow blood samples of patients with ovarian cancer. We will use a previously described (Bonertz et al, 2009) antigen specific T-Reg assay, which has been already established on probes of healthy patients in our lab. 

The above proposed project will be an important module to select the suitable peptides for the planned vaccine trial in ovarian cancer patients.


Associated Member: Armin Rabsteyn

Name:

Armin Rabsteyn

Project:

DKTK (German Cancer Consortium)

Supervisor:

Stefan Stevanović

Email

Opens window for sending emailArmin.rabsteyn(@)web.de

Associated:

01.10.2012 - 31.05.2015

Abstract

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MD scholarship holder: Todor Popov
Associated Member: Todor Popov

Name:

Todor Popov

Project:

A13

Supervisor:

Julia-Stefanie Frick

Email

Opens window for sending emailtodor.popov(@)student.uni-tuebingen.de

Scholarship:

01.04.2014 - 30.09.2014

Associated:

01.10.2014 -28.02.2015

Abstract:

Shot gun proteomics to identify differential DC signaling pathways upon stimulation with commensal bacteria

 

It is widely believed that in Inflamatory bowel diseases (IBD)  like Crohn‘s disease   the mucosal immune system interacts  inappropriately with the commensal microbiota, which results in a homeostasis disruption. However, no particular microbial species has been consistently well-associated with IBD. There are some species in the gut which induce severe inflamation like E.coli and some, which have been shown to prevent  an intestinal inflamatory host response like B. vulgatus. Both of the species interact differently with the immune system and in particular with the DCs, modulating their maturation. Data from previous researches suggest that dendritic cell maturation plays and important role in the maintenance of intestinal homeostasis. However, there is scarce information about the intracellular processes and pathways behind different states of dendritic cell maturation. In our current work, by using the powerful tool of proteomics, we aim to delineate the intracellular pathways leading to semi-mature and mature states of DCs, induced by B.vulgatus and E.coli respectively.


Associated Member (Guest): Carmen Malaval

Name:

Carmen Malaval

Project:

C11

Supervisor:

Tobias Feuchtinger

Email:

Opens window for sending emailcarmen.malaval(@)student.uni-tuebingen.de

Status:

PhD-student

Associated:

01.08.2014 - 31.03.2015

Abstract:

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MD scholarship holder: Joseph Kauer
Associated Member: Joseph Kauer

Name:

Joseph Kauer

Project:

C14

Supervisor:

Hans-Georg Rammensee / Gundram Jung

Email

Opens window for sending emailjoseph.kauer(@)student.uni-tuebingen.de

Scholarship:

01.04.2014 - 30.09.2014

Associated:

01.10.2014 -28.02.2015

Abstract:

Assessing lytic activity of antibodies via flow cytometry using autologous immune cells and freshly isolated tumor cells

In the Section for Experimental Antibody Therapy genetically optimized antitumor antibodies are developed. Usually such antibodies are characterized, among others, by cytolysis assays with cultivated tumor cell lines and allogeneic immune effector cells. However, these assays possess an inherent weakness: Killing of cultivated tumor cells by allogeneic effector cells may deviate significantly from the lytic activity of autologous effector cells against freshly isolated tumor cells.

We will therefore use physiologically relevant conditions when assessing the anti-tumor activity of our antibodies: using isolated peripheral blood mononuclear cells from leukemia patients contaminated with a variable number of leukemic blasts allows the evaluation of antibody activity under “physiological” conditions. Reduction of leukemic cells in these assays will be measured by flow cytometry.

Several mono- and bispecific antibodies are to be tested both, in the presence and absence of pharmaceutical compounds affecting antibody activity, such as steroids and cytokine blockers.


PhD scholarship holder: Lena Hartl (nee Joachim)
Associated Member: Lena Hartl (nee Joachim)

Name:

Lena Hartl (nee Joachim)

Project:

C06

Supervisor:

Tobias Feuchtinger

Email:

lenajoachim(@)gmx.de

Scholarship:

15.06.2011 - 14.06.2012

Associated:

15.06.2012 -31.03.2015

Abstract:

Standardized GMP-Grade ex vivo generation of antigen-specific T cells against multiple viruses in a single step approach for adoptive T-cell transfer after allogeneic stem cell transplantation

Opportunistic viral infections after allogeneic stem cell transplantation (SCT) can cause serious morbidity and mortality. Most viral infections after stem cell transplantation are caused by human cytomegalievirus (HCMV), human adenovirus (HAdV) and Epstein-Barr-virus (EBV). Unfortunately, the treatment with common pharmacologic agents has limited efficacy and relevant toxicity.
Adoptive T-cell transfer turned out to be an attractive approach in viral infections after allogeneic stem cell transplantation. Virus-specific T cells can be isolated out of the blood of healthy donors by ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with immunodominant T-cell epitopes of the several viruses. The virus-specific T cells can now be enriched using IFNγ capture technique and infused into the recipient. Existing ex vivo protocols have been established for the generation of mono-specific ADV-, EBV- or CMV-specific T cells. For each single pathogen a separate blood donation was necessary. Clinical treatment of multiple pathogens has only been possible in protocols using long term in vitro expansion steps, with a significant time delay of adoptive T-cell transfer and has not been available for the treatment of viral complications post SCT so far.
Our aim is to develop a standardized good manufacturing practice (GMP)-grade ex vivo generation of antigen-specific T cells against multiple viruses in a single step approach for adoptive T-cell transfer after allogeneic stem cell transplantation. Adoptive T-cell transfer should be possible out of one blood donation in a GMP-compatible single step approach. Further benefit is a short in vitro protocol to save time and a standardized, less labour-consuming protocol for clinical application in multiple centres. Furthermore, multi-virus specific T cells are an ideal treatment for prophylactical application to prevent viral disease after allogeneic stem cell transplantation. In addition regulatory requirements have to be included into the protocol, for future clinical trials with multi-virus specific T cells.

 


MD scholarship holder: David Gorodezki
Associated Member: David Gorodezki

Name:

David Gorodezki

Project:

C11

Supervisor:

Tobias Feuchtinger

Email

Opens window for sending emailDavid.gorodezki(@)gmail.com

Scholarship:

01.04.2014 - 30.09.2014

Associated:

01.10.2014 -31.03.2015

Abstract:

Molecular mechanisms of T cell co-stimulation and co-inhibition between pediatric ALL blasts and antigen specific T cells induced by bispecific T-cell-engaging antibody MT103

Refractory relapse of B-precursor acute lymphoblastic leukemia (ALL) after allogenic hematopoetic stem cell transplantation is associated with a dismal prognosis, requiring more efficacious strategies for the treatment of B-cell malignancies.

MT103 (Blinatumomab) is a single-chain bispecific antibody construct with specificity for CD19 and CD3, which belongs to the class of bispecific T cell engagers, and potentially activates all cytotoxic T cells of a patient for tumor cell lysis. Although first clinical studies have shown promising results, crucial parameters differentiating responders from non-responders are yet to be identified.

Previous tests have shown various dose-dependent effects of MT103 on cytotoxicity, activation and proliferation of T cells as well as on the expression of various inhibitory molecules (PD1, CTLA4, LAG3, TIM3), which could be the cause of non-response. In our current work, we aim to identify the mechanisms of co-stimulation and co-inhibition on tumor cell lysis by using comparative T cell functional assays.


Associated Member: Dominik Bloes

Name:

Dominik Bloes

Project:

A03

Supervisor:

Andreas Peschel

Email

dominik.bloes(@)med.uni-tuebingen.de

Status:

PhD student

Associated:

01.04.2011 - 31.10.2014

Abstract:

The human innate immune system encounters bacterial challengers every day and antagonises them by multiple antimicrobial mechanisms including the generation of polymorphonuclear leukocytes (PMN), which represent the most efficient phagocytes. Amongst others, the human formyl peptide receptor 2 (FPR2) belongs to the family of seventransmembrane G-protein coupled receptors and is expressed by PMN. In recent studies, it could be shown that FPR2 is obligatory for recruiting and activating PMN in staphylococcal infections as it recognises concentrations of the major staphylococcal cytolysins, the phenol-soluble modulin (PSM) peptides [1]. Moreover, FPR2 adjusts the PMN response regarding both the amount of PSM peptides released and the pathogenicity of staphylococcal species [2]. The aim of my thesis is to identify further FPR2 ligands synthesised by human pathogenic bacteria and to elucidate whether FPR2 is also able to differentiate between those as shown for diverse staphylococcal species. Moreover, we are interested in the expression pattern of FPR2 on other human cells and their FPR2-specific response towards staphylococcal challenge.

[1] Kretschmer D, Gleske AK, Rautenberg M, Wang R, Köberle M, Bohn E, Schöneberg T, Rabiet MJ, Boulay F, Klebanoff SJ, van
Kessel KA, van Strijp JA, Otto M, and Peschel A, Human Formyl Peptide Receptor 2 Senses Highly Pathogenic Staphylococcus aureus,
Cell Host Microbe (2010).
[2] Rautenberg M, Joo HS, Otto M, and Peschel A, Neutrophil responses to staphylococcal pathogens and commensal via the formyl
peptide receptor 2 relates to phenolsoluble modulin release and virulence, FASEB J (2011).


Associated Member: Julia Steinhilber

Name:

Julia Steinhilber

Project:

B08

Supervisor:

L. Quintanilla-Martinez de Fend / F. Fend

Email:

Opens window for sending emailjulia.steinhilber(@)med.uni-tuebingen.de

Status:

PhD-student

Scholarship:

Associated:

15.09.2013 - 31.10.2014

Abstract:

Identification of miRNA expression patterns in ALK+ ALCL

Anaplastic large cell lymphoma (ALCL) represents a distinct type of non-Hodgkin lymphoma and it is classified in two different disease entities - ALK+ and ALK- ALCLs. ALK+ ALCLs carry a translocation (2;5) that leads to the constitutive activation of ALK tyrosine kinase. The oncogenic NPM-ALK activates several downstream signaling pathways, which participate in cell proliferation, differentiation and survival. One central downstream target of ALK is the leucine zipper transcription factor CCAAT/enhancer binding protein beta (C/EBPβ). C/EBPβ is involved in a number of cellular processes, including differentiation, proliferation, inflammatory responses and metabolism. Moreover it has been associated with tumorigenesis in solid tumors and plays an important role in ALK+ ALCL oncogenesis. In recent years several groups have shown that several miRNAs are differentially expressed in ALCL and seem to be involved in cell growth, survival and immune response. The so far reported posttranscriptional regulation potential of C/EBPβ in several systems, raised the question in which extent C/EBPβ controls miRNA expression in ALK+ ALCL cells. MiRNAs are involved in many important biological processes including the control of various activities of the immune system and different stages of hematopoietic development, the regulation of cellular differentiation and apoptosis. In tumors, deregulated miRNAs are able to drive oncogenesis acting as tumor suppressors or oncogenes. Thus, the aim of this study is first to analyze the differential expression of miRNAs between ALK+ and ALK- ALCLs using next generation sequencing and to generate C/EBPβ-dependent miRNA profiles, and second to characterize some of the identified miRNAs and their specific target genes. The identification of microRNAs that are deregulated in ALCL will offer new insights into the biology of ALCL and opens new treatment options for the future.


Associated Member: Alexandr Kuranov

Name:

Alexandr Kuranov

Project:

from the Graduate Center of the Medical Faculty (School of Immunology)

Supervisor:

Claudia Müller

Email:

Iskander.kuranov@gmail.com

Status:

PhD-student

Associated:

01.04.2012 - 31.10.2014

Abstract:

Immunogenetics of Behçet’s disease: Interaction of HLA class I molecules and KIR receptors with LILR on cells of the innate immune system.

Our group has investigated an immunogenetic role of HLA genes and regulation of the interaction between granulocytes and HLA molecules and LILR ligands in Behçet's patients and healthy individuals. The research was focused on HLA-B*5101 molecule, which is thought to be involved in the pathogenesis of the Behçet's disease. It has been postulated that migration of monocytes and granulocytes during early stages of typical ulcer is stimulated in response to stimulatory molecules of epithelial and/or endothelial origin.  This might be due to a regulatory role of NK cells, which are controlled via HLA-binding receptors. Therefore, one must first determine whether patients with Behçet's disease differ with the respect of expression of KIR family on NK cells and HLA-B*5101-binding receptors including those of the LILR family expressed on myelomonocytes as well as on the other cell types. The impact of cytokines such as IL-17 and interferon gamma on the expression of these molecules is to be investigated.


Associated Member: Ellen Brenner

Name:

Ellen Brenner
(Organisation Internat. Symposium: "Moving forward in Immunology" Oct. 2012)

Project:

C01

Supervisor:

Martin Röcken

Email:

Ellen.Brenner(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2011 - 01.10.2014

Abstract:

TLR-mediated inflammation promotes matastasis of B16-melanoma

Toll-like receptor (TLR) stimulation was primarily developed as anti-tumor therapy. More recent data implicated TLR stimulation in the transition of pre-malignant lesions into cancer and outgrowth of metastases. Thus, TLR signaling can either promote or inhibit tumor growth and metastasis. Yet, the role of TLR on tumor progression and seeding of metastatic tumor cells is still unclear. Subcutaneous injection of B16 melanoma cells significantly induced TLR2, -4, -7 and -9 expression, with different expression patterns on day 5, 12 and 14. To determine whether this signaling was of biological relevance we transplanted the tumor into MyD88.ko-mice, deficient in TLR-signaling. MyD88.ko-mice had a 60 % reduced tumor growth, and 4/18 tumors did not grow. As a second model we analyzed seeding of B16 melanoma cells after intravenous injection and found after 24 and 48 hours a significant up-regulation of TLR4 and TLR7 in the lung tissue. As negative control we injected equal numbers of mononuclear cells. We used this model to identify the compartment responsible for the increased TLR expression. We separated tumor cells from lung tissue cells via FACS, 24 and 48 hours after intravenous injection of DiD-labeled B16 melanoma cells. The data revealed host derived cells as the main source of TLR expression in metastatic lungs. Thus, by initiating TLR-signaling tumor cells may create a milieu that promotes their own seeding.


Associated Member: Diana Gransheier (nee Meckbach)

Name:

Diana Gransheier (nee Meckbach)

Project:

B01

Supervisor:

Jürgen Bauer

Email:

diana.meckbach(@)web.de

Status:

PhD-student

Associated:

01.04.2011 - 01.10.2014

Abstract:

Systems Biology of Immune Escape


The Hgf-Cdk4R24C melanoma mouse model shows successful tumor control after transfer of antigen-specific T-cells at first, yet secondary immune escape develops rapidly. One major factor contributing to escape is the genetic and genomic instability of solid tumors, which has been called the “mutator phenotype” of cancer. This instability largely influences tumor development, potential therapeutic targets, and mechanisms of resistance to therapy. By selection of primarily stochastic events, it offers the tumor major flexibility during progression and adaption to changed tumor environments such as immunotherapy.
We analyze mechanisms of tumor immune escape in a number of tumors subjected to immunotherapy in the Hgf-Cdk4R24C mouse model using comparative genomic hybridization, expression arrays, candidate gene sequencing, and systems biological analysis. Comparison of the genomic make-up of tumors before and after development of resistance will allow identification of molecular genetic changes that are likely to be related to immune escape. We expect to show that mechanisms of immune escape affect a limited number of pathways on different levels, and that by targeting these pathways the effect of the immunotherapy can be reinstated. Based on this understanding, we intend to develop prediction methods for immune escape mechanisms in order to improve immunotherapy


Associated Member: Christian Hotz

Name:

Christian Hotz

Project:

C05

Supervisor:

Stefan Stevanović

Email:

Opens window for sending emailchrishotz(@)gmx.de

Status:

PhD-student

Associated:

01.07.2013 - 01.10.2014

Scholarship:

Abstract:

xxx

xxx


Associated Member: Julia Steinbacher (nee Hilpert)

Name:

Julia Steinbacher (nee Hilpert)
(
Organisation Internat. Symposium: "Moving forward in Immunology" Oct. 2012)

Project:

once GK 794

Supervisor:

Helmut R. Salih

Email:

Julia.Steinbacher(@)med.uni-tuebingen.de

Status:

PhD-student

Scholarship:

01.01.2010 - 31.03.2012 (GK 794)

Associated:

01.04.2012 - 31.03.2014

Abstract:



Associated Member: Michaela Renner-Schneck

Name:

Michaela Renner-Schneck

Project:

B03

Supervisor:

Thilo Stehle

Email:

michaela.schneck(@)uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2011 - 01.10.2013

Abstract:

Crystallization and Structural Characterization of the Complex between the HCMV Immunoevasin UL16 and the NKG2D-ligand ULBP2

Human cytomegalovirus (HCMV) infection results in down-regulation of MHC class I proteins and induction of NKG2D ligand expression triggering NK-cell cytotoxcicity towards infected cells.The HCMV immunoevasin UL16 however counteracts surface expression of several NKG2D ligands by intracellular sequestration. Interestingly, UL16 interacts with MICB, but not with the closely related MICA, as well as with UL16-binding proteins (ULBP) ULBP1 and ULBP2, which are only distantly related to MICB, but not with ULPB3 or ULBP4, although all constitute ligands for NKG2D. [3]
It has been shown that UL16 discriminates MIC molecules by their a2 domains [3] and thus mimics a central binding motiv of the NKG2D immunoreceptor. This led to the thesis that the MIC-molecules and ULBPs that do not interact with UL16 might have evolved as UL16 “escape variants” under the selective pressure of viral immunoevasins [1]. The the crystal structure of the UL16-MICB further supports the thesis [2] but so far no structural data is available for the interaction between UL16 and ULBP2 which would be an important verification of the above model. Consequently the aim of my phD-project is the crystallization and structural characterization of HCMV immunoevasin UL16 – NKG2D-ligand ULBP2 complex.

[1] Jessica Spreu, Thilo Sthele and Alexander Steinle; Molecules by Their _2 Domains1 “Human Cytomegalovirus-Encoded UL16 Discriminates MIC; Journal of immunology 177: 3143-3149; 2006.
[2] Steffen Müller, Structural and functional characterization of the protein-protein interaction between the HCMV immunoevasin UL16 and the NKG2D ligand MICB; Dissertation der Fakultät für Chemie und Pharmazie der Eberhard Karls Universität Tübingen zur Erlangung des Grades eines Doktors der Naturwissenschaften, 2010


Associated Member: Andreas Maurer

Name:

Andreas Maurer

Project:

B02

Supervisor:

Hubert Kalbacher

Email:

andr3asmaur3r(@)googlemail.com

Status:

PhD-student

Associated:

01.04.2011 - 31.08.2013

Abstract:

PROCESSING OF THE MHC CLASS II-ASSOCIATED INVARIANT CHAIN

To allow for the presentation of peptide antigens on MHC class II by professional antigen presenting cells (APC) to helper T cells, the chaperone “invariant chain“ (Ii, CD74) is degraded stepwise on its way to MHC class II loading compartments. Several cysteine cathepsins are involved in this process as intermediate products accumulate upon inhibition by leupeptin or E64 in cell culture. However, the intitial cleavage which leads to an intracellular accumulation of a 22 kDa intermediate form of Ii is not affected by cysteine protease inhibitors and the protease responsible for this step is not yet identified. Also the cleavage site of this protease is poorly defined. Aim of the work is the elucidation of the early cleavage pathway of this key protein in MHC class II restricted antigen presentation.
Since involvement of pepstatin sensitive proteases other than Cathepsin D and E in the initial Ii cleavage has been reported, we also further characterize Napsin A expression in human and murine antigen presenting cell subsets and the biochemical properties of Napsin A.
For the confirmation of the identified cleavage pathway, we also develop an in vitro system to cleave Ii bound to an immobilized MHC class II dimer.


Associated Member: Sabine Braun

Name:

Sabine Braun

Project:

C02

Supervisor:

Susanne Rittig

Email:

Opens window for sending emailsa.braun@student.uni-tuebingen.de

Status:

MD-student

Associated:

15.06.2012 - 31.08.2013

Abstract:

Osteactivin, also known as transmembrane glycoprotein NMB (GPNBMB) and dendritic cell-associated transmembrane protein  DC-HIL is a typical transmembrane  glycoprotein detected abundantly in dendritic cells, but not or only at low levels in monocytes. Its expression on antigen-presenting-cells can inhibit T-cell-activation by binding the type-I-transmembrane proteoglycan syndecan-4 on T-cells.
We study the influence of different therapeutically used immunosuppressive reagents such as the corticosteroid Prednisolon, the calcineurin inhibitors Tacrolimus and Cyclosporin A as well as the macrolid Rapamycin on the expression of Osteoactivin in human monocyte-derived dendritic cells.


Associated Member: Zora Teltschik

Name:

Zora Teltschik

Project:

A09

Supervisor:

Jan Wehkamp

Email:

Zora.Teltschik(@)ikp-stuttgart.de

Status:

PhD-student

Associated:

01.04.2011 - 30.06.2013

Abstract:



Associated Member: Jens Schreiner

Name:

Jens Schreiner

Project:

A03

Supervisor:

Stella Autenrieth

Email:

Jens.Schreiner(@)medizin.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2011 - 31.03.2013

Abstract:

Modulation of dendritic cell function by Staphylococcus aureus PSM peptides

Virulence of the newly emerging community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and other highly pathogenic S. aureus depends on Phenol-Soluble Modulin (PSM) peptide toxins, a group of virulence factors that are known to attract and lyse neutrophils. In human cells PSM peptides exert their function by binding to the Formyl-peptid Receptor 2 (FPR2). We demonstrate that the murin homologue mFPR2 is expressed on mouse bone marrow-derived dendritic cells (BM-DC), which makes them a possible target for PSM peptides. It is described [1] that ligands of formyl-peptid receptors can inhibit dendritic cell maturation. We will analyze the effect of PSM peptides on dendritic cells during maturation, looking on the expression of costimulatory molecules and the secretion of cytokines. We also plan to characterize antigen uptake of PSM-peptide treated DCs, focussing on endocytosis, phagocytosis and macropinocytosis. A further aim of the project is to do a detailed characterization of the T-cell response induced by PSM peptide treated DCs. After analyzing the effects of PSM-peptides in in vitro assays we will transfer our results towards an in vivo mouse model.

[1]Kang,H.K. et al. (2005) The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2. J. Immunol. 175, 685-692.


Associated Member: Christoph Griessinger

Name:

Christoph Griessinger

Project:

B06

Supervisor:

Bernd Pichler

Email:

Christoph.Griessinger(@)med.uni-tuebingen.de

Status:

PhD-student

Associated:

01.04.2011 - 30.03.2013

Abstract:



MD scholarship holder: Sebastian Hörber
Associated Member: Sebastian Hörber

Name:

Sebastian Hörber

Project:

B07

Supervisor:

Klaus Schulze-Osthoff

Email

sebastian.hoerber(@)googlemail.com

Scholarship:

01.02.2012 - 31.07.2012

Associated:

01.08.2012 - 31.03.2013

Abstract:

Functional relevance of the novel IkappaB-protein, IκB-zeta, for the inflammatory response of macrophages in chronic inflammatory bowel diseases

Macrophages are one of the major components of the innate immune system and exert a variety of functions, including phagocytosis, killing of microbes and tumor cells and antigen presentation to lymphocytes. One important property of macrophages is the migration into inflamed tissue. This migration is remarkably increased in inflammatory bowel diseases such as Crohn’s disease and Colitis ulcerosa.
Inhibitor of kappa B-zeta (IκB-zeta), a novel IκB protein with unusual properties, is highly expressed in activated macrophages. It is a nuclear protein which is involved in transcriptional regulation of secondary response genes, such as IL-6 or IL12b, after toll-like receptor stimulation. To elucidate further influences of IκB-zeta on macrophages, we will compare bone-marrow derived macrophages from wild type and IκB-zeta knockout mice. The functional relevance of IκB-zeta for the regulation of macrophages will be investigated in phagocytosis and migration assays. Also we plan to identify new target genes of IκB-zeta. Additionally, expression of IκB-zeta will be studied in biopsies from patients suffering from Crohn’s disease or Colitis ulcerosa to examine a possible involvement of IκB-zeta in these diseases.


MD scholarship holder: Annika Horrer

Name:

Annika Horrer

Project:

C03

Supervisor:

Peter Lang

Email:

Annika.Horrer(@)student.uni-tuebingen.de

Status:

MD-student

Associated:

01.04.2012 - 31.01.2014

Scholarship:

01.09.2012 - 31.01.2013

Abstract:

In vitro examination of anti-leukemic NK-cell subpopulations in view of their ability for lysis of primary pediatric ALL blasts

Natural killer cells play a fundamental part in hematopoietic stem cell transplants, by facilitating the engraftment of the transplant. Furthermore, NK cells show anti-leukemic properties and thereby are thought to contribute immunologically to prevent leukemic relapse after stem cell transplantation. This thesis aims at testing NK cell subpopulations in view of their cytotoxic activity against leukemic cell lines and primary pediatric B-ALL blasts. Further to generate ex vivo large amounts of NK cells with high antileukemic activity from haplo-identical donors on a regular basis for cellular targeted therapy.


MD scholarship holder: Kerstin Artzner

Name:

Kerstin Artzner

Project:

C05

Supervisor:

Stefan Stevanović

Email

kerstin.artzner(@)student.uni-tuebingen.de

Scholarship:

01.03.2012 - 31.08.2012

Abstract:

Identification and characterization of immundominant HLA-B*44-restricted peptide epitopes of HAdV species C

Adenoviruses  infecting  humans  belong  to  the  genus  Mastadenovirus  and  are  divided into seven species (species A to G) and further into 53 serotypes (Ad1 to Ad53).  The most prevalent one is serotype C2 (18.6%).
Adenoviral  infections  are  common and widespread causing symptoms as upper  and  lower respiratory  tract  illnesses, gastrointestinal diseases, myocarditis, hepatitis, acute  follicular  and  epidemic keratoconjunctivitis.  Studies report  that about 3%  of  infections  in  a  civilian  population  are due  to  adenovirus.  Besides the mild and self-limiting infections, adenovirus is described in immunocompromised individuals to lead to severe pathogenesis with a mortality rate  of  up  to 76%.
Immunocompromised  individuals highly  at  risk  are  young children, bone marrow  or  other  transplant  patients receiving high  doses  of  immunosuppressive drugs,  cancer  patients  undergoing  chemotherapy  or  radiation,  and  AIDS patients.  In  transplant  patients,  the  most  prevalent species are serotypes  HAdV 2, HAdV 5 and in cancer  patients  are  more  often  afflicted  by  HAdV 1,  HAdV 5. 
Adenovirus  can  establish  a  persistent  presence  in  its  host  for  a  long time  after  clinical  symptoms  have  subsided which could be an  explanation  to  the  source  of  endogenous  virus  infection  in  patients once the immune system function has been impaired. Low T  cell  counts  have  been  shown  to  correlate with severity of infection and mortality. Therefore adenovirus  is  a  serious  problem  in  immunocompromised patients.
The prevalence  of  adults  in the  general  population that  have  endured  adenoviral  infection  in  their  life  and therefore possess memory CTL varies between  65%  and  100%. Accordingly a sufficient amount of PBMCs of healthy donors exhibited significant proliferative responses to HAdV virions. In this study we follow the strategy  of  reverse  immunology  to identify CTL  epitopes  of several adenoviral  proteins restricted  by  HLA super-type B*44 donors and characterize their  dominance and frequency  of  immune response. 
Identified immunological epitopes could be relevant for immunotherapy  with  stimulated  autologous adenovirus-specific  T  cells  or  to develop peptide vaccines in order to  cope  with  these serve infections.


Associated member: Hanna Kreil

Name:

Hanna Kreil

Project:

C03

Supervisor:

Peter Lang

Email:

hanna-lisa.kreil(@)student.uni-tuebingen.de

Associated:

01.04.2011 - 29.02.2012

Abstract:

Relevance of  flow cytometry with anti HLA-antibodies for prediction of  graft rejection after haploidentical stem cell transplantation (HSCT) in children

For nearly 70% of the patients in need of a stem cell transplantation no HLA- identical related donor can be found. Looking for a suitably matched unrelated donor would be time consumable or such a donor does not exist at all. Therefore haploidentical related donor stem cell transplantation is a promisimg alternative. Problems of HLA- mismatched transplantation are the HLA barrier (for engraftment),  graft -versus -host disease (GVHD) and transplantion-related mortality (TRM) by intensive conditioning regimens and hesitant T cell recovery.
Flow cytometry using anti HLA-antibodies sensitivly monitors T cell chimerism after SCT. Our aim is the investigation of  fluorescence-activated cell sorter (FACS) analysis of pediatric patients to obtain and possibly predict patterns of (pending) graft rejection. Early diagnosis should make an effective management possible, for instance infusion of donor lymphocytes (DLI) or  reducing immunosuppressive drugs. The effectiveness of such approaches is also observed.


Associated member: Christina Kyzirakos

Name:

Christina Kyzirakos

Project:

C05

Supervisor:

Stefan Stevanović

Email:

christina.kyzirakos(@)gmx.de

Status:

PhD-student

Associated:

01.04.2011 - 29.02.2012

Abstract:



MD scholarship holder: Siona Pfeffer

Name:

Siona Pfeffer

Project:

C03

Supervisor:

Peter Lang

Email

Stephanie-Siona.Pfeffer(@)student.uni-tuebingen.de

Scholarship:

01.07.2012 - 31.07.2012 (aborted)

Abstract:

The impact of the FcγRIIIA-158V/F (CD16) polymorphism on NK cell mediated ADCC using a third-generation anti-CD19 antibody in the treatment of pediatric acute lymphoblastic leukemia of the B lineage

.


Associated member: Johanna Reichel

Name:

Johanna Reichel

Project:

A08

Supervisor:

Christian Sinzger

Email:

Johanna.Reichel(@)med.uni-tuebingen.de

Associated:

01.04.2011 - 29.02.2012

Abstract:



MD Scholarship holder: Moritz Schiemer

Name:

Moritz Schiemer

Project:

B02

Supervisor:

Claudia A. Müller
Hubert Kalbacher

Email

moritzschiemer(@)hotmail.com

Scholarship:

01.04.2011 - 30.09.2011

Associated:

01.10.2011 - 29.02.2012

Abstract:

Expression of HLA-Bw4/Bw6 in human thymus: differences in cortex and medulla

Immature T-cells undergo positive selection for a functional T-cell-receptor in the thymic cortex, whereas the medulla is specialized for negative selection deleting self-reactive cells. MHC-peptide complexes are the major determining ligands in these selection processes. Recent studies in the mouse indicate the existence of cortex-specific proteases permitting a distinct peptide repertoire as MHC-ligands for positive selection. Similarly presence of medulla specific transcription of peptides by AIRE has been shown. This points to differences in the selecting MHC-peptide ligands in the cortex and medulla, which could be relevant for the development/shaping of a T-cell repertoire more or less prone for self-reactivity. Preliminary immunohistological analyses of specific private versus public HLA-determinants (Bw4/Bw6 versus common HLA-B epitopes) in our group also support this hypothesis. My thesis focuses on the further evaluation of differences of MHC-peptide complexes in the medulla versus cortex of the human thymus. Immunohistological and biochemical analyses with the use of monoclonal antibodies against various epitopes of the same HLA molecules are applied.


 

 

MD Scholarship holder: Elina Barsaume

Name:

Elina Barsaume

Project:

C05

Supervisor:

Stefan Stevanović

Email

e.barsaume(@)googlemail.com

Scholarship:

01.04.2011 - 30.09.2011

Associated:

01.10.2011 - 29.02.2012

Abstract:

T cell epitopes from antigens of Epstein-Barr-Virus

Nearly 95% of the adult population are infected with Epstein-Barr-Virus (EBV). The infection of immunocompetent individuals normally remains asymptomatic whereas severe complications are possible in an immunocompromised organism, e.g. after organ transplant. Knowledge of immunogenic EBV antigens shall serve as basic strategy for vaccination and adoptive immunotherapy. From the sequences of twelve EBV antigens using epitope prediction via the programme SYFPEITHI peptides are selected for the HLA-restriction A*26. Up to now there is no dominant epitope known. Healthy, HLA matched donors (PBMCs) are tested by ELISpot regarding a reaction to the predicted peptides. Additional T cell assays shall characterize specificity, identity and cytokine secretion of the leukocytes showing a reaction to the dominant epitopes. Therefore FACS analysis will take place. To detect a potential supertype, dominant epitopes will be tested again by using PBMCs that are negative for the relevant HLA but positive for related allotypes. A supposed relation between HLA-A*01 and A*26 is thus investigated. For further characterization of the T cells classical markers such as CCR7 or CD45RA/RO will be determined and the cells will be classified into effector/memory categories. The secretion of further cytokines besides IFNγ will be analyzed as well.


 

 

MD Scholarship holder: Elisabeth Mortha

Name:

Elisabeth Mortha

Project:

C10

Supervisor:

Hans-Jörg Bühring

Email

elisabeth.mortha(@)student.uni-tuebingen.de

Scholarship:

01.04.2011 - 30.09.2011

Associated:

01.10.2011 - 29.02.2012

Abstract:

Prospective isolation of mesenchymal and epithelial stem cells (MSC and ESC) from the amniotic membrane of human placenta and analysis of their differentiation potential

The amniotic membrane is an avascular membrane on top of the placenta consisting of a single layer of amniotic epithelial cells and a stromal layer beneath. The stromal layer is derived from the extraembryonic mesoderm, whereas the epithelial layer is formed by pluripotent epiblast cells. Supported by several reports amniotic epithelial stem cells are able to differentiate into all three germ layers consisting of ectoderm (neurons, astrocytes, glia), mesoderm (osteocytes, adipocytes, cardiomyocytes, myocytes) and endoderm (hepatocytes, pancreatic cells). Because of the almost unlimited differentiation potential and the ethically unobjectionable availability, human placenta may be an attractive source for cell therapy-based applications and regenerative medicine.
In the proposed project, I intend to isolate and characterize stem cells of amniotic membrane of placenta. Cells will be stained by immunofluorescence  and isolated by fluorescence activated cell sorting. The sorted cells will be analyzed for their antigen expression profile, their clonogenic capacity (CFU assays) and their differentiation potential.


 

 

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