HIV-infected H9 T cell

Future Topic: Immunology & Inflammation

The Initiative and Networking Fund of the Helmholtz Association

The Initiative

Five Helmholtz Centers are joining forces in a new initiative that aims to advance immunology research and the development of new therapies. The MDC is coordinating the long-term project, which was launched in November 2017 with a three-year program.

There is a mood of optimism among the immunology community, because the past few years have seen great strides made in immune system research. The first immunology therapies have been approved, while others are being tested in clinical trials. Researchers are uncovering ever more details about the complex system of organs, tissues, and different cell types that make up the human immune system.

The initiative entitled “Immunology & Inflammation” brings together immunology research – which is spread out over various Helmholtz Centers – in a common structure. Of twenty projects, six are organized as “tandem” projects in which laboratories of different Centers work closely together.

MDC researchers Michela Di Virgilio and Klaus Rajewsky are leading and coordinating the initiative. It is the nucleus for an undertaking that intends to position the Helmholtz Association as a main player in application-oriented immunology research internationally.

Key scientific questions addressed by the initiative

  • How is the tissue specificity of immune cells generated and how is it affected by environmental influences, plasticity and the tissue microenvironment? 

  • What is the mechanistic link between infections, immune reactions and their microenvironment, inflammatory responses and central nervous system disorders, including neurodegenerative disease, and how can we use this information to better understand and treat these disorders? 

  • How can our knowledge of the immune system be applied to develop innovative therapies, including the identification of novel antigens for immune therapies and gene repair strategies in monogenic immune diseases?

The Helmholtz Centres have a broad repertoire of state-of-the-art technologies and expertise to work on these topics. Examples are CRISPR/Cas9-mediated mutagenesis, genetic mouse models, cell-fate-mapping, organoids and tumor explants, as well as GMP production of pharmaceuticals and many years of experience in conducting clinical studies.

Aside from new and joint research projects, the training of the next generation of basic and clinical researchers in immunology, as well as scientific exchange, is also in the focus of the future topic.

Featured picture: Scanning electromicrograph of an HIV-infected H9 T cell. Credit: NIAID, cc-by-2.0

Team

These 23 research teams are taking part in the initiative:

Max Delbrück Center for Molecular Medicine (MDC)

The MDC is devoted to understanding the molecular basis of health and disease, with a focus on disease mechanisms at a system-wide level and the translation of findings into clinical applications.

It cooperates closely with Charité, a large university hospital in Berlin. Joint institutions include the Experimental and Clinical Research Center (ECRC ) und the Berlin Institute of Health (BIH ).

One of the research areas at the MDC is immunology and inflammation, which covers tumor immunology, DNA repair in B lymphocytes, the role of tumor stroma-immune cell interaction in cancers, the role of innate immune cells in gliomas and neurodegenerative diseases, and the development of immunotherapy strategies.

The MDC’s participating research groups bring a broad range of technological expertise to the initiative – ranging from biochemical assays, structure and function analysis, and gene editing to the development of preclinical mouse models, GMP production, and even clinical trials.

German Cancer Research Center (DKFZ)

The DKFZ is a multidisciplinary center covering cancer biology from basic molecular and cell biology to clinical research and care.

Through the National Center for Tumor Diseases, a joint venture between the DKFZ, Heidelberg University Hospital, and German Cancer Fund, the DKFZ has access to patients for research from bench to bedside and back. The participating groups of the DKFZ bring in broad expertise in fundamental and clinical tumor immunology, the link between cancer, chronic inflammation and viral infection, neuroimmunology, and immune surveillance of tumors.

The center will contribute technological expertise crucial to the success of the proposal, such as the generation and characterization of pre-clinical mouse models, in vivo fate mapping, GMP production, and innovative clinical trials.

German Center for Neurodegenerative Diseases (DZNE)

The DZNE focuses on neurodegenerative disease, covering both research on the fundamental molecular and cellular basis of neurodegenerative disease as well as clinical and population research.

The participating groups cover an especially exciting area of research, namely the link between innate immune and inflammatory mechanisms to neurodegenerative disease. The center will provide expertise on profiling neurodegeneration, neuroinflammation and neuronal function including in vivo imaging, CNS histology, generation of human-derived cellular models, and their functional assessment under physiological and pathological circumstances.

Helmholtz Zentrum München (HMGU)

The HMGU aims to contribute significantly to a better understanding of major non-communicable common diseases which develop from lifestyle, environmental factors and personal genetic background, most notably diabetes and allergy.

The overall goal of HMGU’s research is to elucidate the complex disease causes and to develop innovative approaches for their precise diagnosis, prevention and therapy. The participating groups bring in their expertise in the basic molecular mechanisms of T cell signaling, activation, and tolerance, as well as T cell immunity and immunotherapy in diabetes, allergy and lung diseases.

The center will contribute important technological expertise in the generation and provision of novel pre-clinical mouse models, tools to fate map tumor cells and immune cells, and a translational approach for CRISPR/Cas9-based gene therapy of monogenic diseases.

Helmholtz Centre for Infection Research (HZI)

The HZI has expertise in the area of infectious diseases, investigating the fundamental principles underlying infection processes to develop innovative approaches to prevent, diagnose and treat infectious diseases.

In this context, the host’s innate and adaptive immune responses to infection, evasion mechanisms that allow pathogens to circumvent the host defenses, and underlying mechanisms of pathogen clearance are dissected.

Within this proposal, the HZI will contribute expertise in epigenetic imprinting for the identification of immune cell subsets, epigenome-editing of T cells using CRISPR/Cas9, predictive mathematical models, mouse behavioral analysis, as well as expertise in clinical trials and GMP production of antibodies and immune cells.

Research

Inflammation processes and interactions between the adaptive and innate immune systems play a major role in both infections and cancers – as well as in nearly every widespread human disease.

Since a comprehensive approach to the immune system would be as complex as the system itself, we concentrate on three interconnected central and timely topics in immunology, which are addressed in three scientific work packages (WP).

WP 1. Tissue-Specific Immune Cells

WP1 concerns the factors that determine the tissue- and organ-specificity of immune cells, a topic that is gaining rapidly increasing attention and may become ever more central in understanding as well as treating immune-related diseases. Decisive factors will be tackled in the following aims:

  1. the genetically determined developmental programs that lead to immune cell specificity and function,
  2. the influence of external (environmental) factors on innate and adaptive immunity and its plasticity,
  3. the effects and mediators of the tissue microenvironment in shaping immune cell functions, and
  4. as a specific example the interplay of tumor microenvironment and cancer cells, which allows the latter to escape immune surveillance.

WP 2. Immunity, Infection and Inflammation in the CNS

WP2 explores a second major example of the impact of a specific environment on the immune system by addressing the characteristics of immunity, infection and inflammation in the central nervous system (CNS), processes that have recently been demonstrated to play major roles in many CNS disorders, notably neurodegeneration, but also neuropsychiatric diseases. Its specific aims concern

  1. functional and regional diversity of microglia, the innate immune cells of the CNS,
  2. microglia-mediated inflammation as a major causative mechanism in neurodegenerative disorders, and
  3. the interplay between infection and neurodegeneration, an interplay that occurs both in CNS-based and peripheral infection.

WP 3. Innovative Therapies

WP3 addresses innovative therapies that result from research of WP1 and WP2 and enables the translation of these findings into the clinic. Based on the first, currently ongoing clinical trials of such innovative therapeutic strategies, notably in cancer, the specific aims of WP3 will cover

  1. harnessing the adaptive and innate immune response against tumors,
  2. the search for and characterization of novel antigens for targeted T cell therapy, the bottleneck in cellular therapies, and
  3. CRISPR-Cas9 mediated gene therapy of monogenic immunodeficiencies as pioneer projects.

Synergies

A key aim of the initiative is to bring together a community of excellent researchers from all centers in the Helmholtz Research Field Health.

Several collaborative efforts within the consortium already exist and have yielded results which could not have been achieved by single research groups. Examples include common studies investigating connections between infections (HZI) and neurodegeneration (DZNE), or studies on the role of inflammation in metastasis and dissemination of tumor cells (DKFZ) and (MDC), as well as the role of chronic inflammation (DKFZ) and programed cell death in controlling DNA damage (MDC).

To enable and foster projects that cannot be done at a single Helmholtz Center, we have enhanced interactions by funding six collaborative projects, i.e. projects implemented by pre- and/or post-doctoral researchers who are supervised by two PIs from different centers:

  • TCR gene therapy of pancreatic cancer through coordinated attack by mutanome-specific CD8+ and p53-specific CD4+ T-cell. Supervisors: Rienk Offringa (DKFZ) and Thomas Blankenstein (MDC)

  • A combined in vitro and in silico analysis of microglia activation to assess the potential of the voltage-gated proton channel HVCN1 as a therapeutic target in Alzheimer’s disease. Supervisors: Melania Capasso (DZNE) and Michael Meyer-Hermann (HZI)

  • Impact of AHR signalling on immunity. From structure to function. Supervisors: Michael Platten (DKFZ) and Oliver Daumke (MDC)

  • Mechanistic analysis of lymphoma-triggered dissemination to brain, liver and lymphoid tissue through crosstalk to stromal cells. Supervisors: Mathias Heikenwälder (DKFZ) and Uta Höpken (MDC)

  • Impact of nasal pollen exposure on the inflammatory milieu within the brain and the control of neurotropic virus infections (NaPo-BRAIN). Supervisors: Claudia Traidl-Hoffmann (HMGU) and Ulrich Kalinke(HZI)

  • Towards therapeutic gene editing in monogenic primary immunodeficiencies. Supervisors: Klaus Rajewsky (MDC) and Ellen Renner (HMGU)

Activities

I & I Covid Symposium

March 3, 2021, virtual

The website will go online shortly.

I & I  3rd Retreat

September 30 - 1. October 2020

The 2020 I&I retreat will be held online. Please, follow the link below to register yourself.

I & I Talks and Lab Visits

 

PhD students and postdocs from the participating labs are invited to go to a partner lab to give a talk and visit the lab.

 

Training Schools

 

PhD students and early-stage postdocs from the participating labs are invited to attend a training school. The project will also cover the attendance to Conferences and Workshops as long as the participant presents a poster or gives a talk. 

Recommended schools:

  • FEBS Immunology Summer School Link 
  • Schools organized by the DGfI Link 
  • Schools organized by the European Network of Immunology Institutes Link 

I & I 2nd Retreat

October 2019, Heidelberg

The info will be available soon.

Satellite Symposium - DGfI Meeting

September 10, 2019, Munich

All I & I researchers are welcome to join the Immunology & Inflammation Satellite Symposium that takes place in Munich on September 10, 2019. The Symposium is organized by Prof. Ellen Renner and Prof. Klaus Rajewsky. 

See the Program here. 

You can access the conference website here. 

1st I & I Conference

February 24-26, 2019, Berlin

Our 1st edition holds an exciting program that comprises four sessions covering the key new developments, their impact on life science, and implications for modern medicine. We have invited scientists among the top world-renowned experts for their standing in the field and contribution to the breakthroughs that fuelled these new areas of investigation. Young scientists will also be given the opportunity to present data through posters and short presentations. 

You can access the conference website here.

I & I 1st Retreat

November 26-27, 2017, Berlin

The I&I kick-off meeting and 1st retreat took place on 26-27 November 2017 at the Conference Venue of the Max Planck Society, Berlin. The consortium principal investigators were invited to shortly share their research work.

The agenda is available here.

Publications

In press, Cell Rep.
53BP1 supports Immunoglobulin Class Switch Recombination independently of its DNA Double-Strand D. Sundaravinayagam et al. 

 

April 2019, J. Neurosci. Res.
Microglial phagocytosis in ageing and Alzheimer´s disease
E. Gabande Rodriguez, L. Keane, M. Capasso

 

April 2019, Nat. Med.
Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer
M. Malehmir, D. Pfister, [...] A. Weber, M. Heikenwalder

 

March 2019, Front Immunol.
Discrepancies in the tumor microenvironment of spontaneous and orthotopic murine models of pancreatic cancer uncover a new immunostimulatory phenotype for B cells
S. Spear, J. B. Candido, [...] H. M. Kocher, M. Capasso

 

March 2019, Allergy 
IL-4 receptor α blockade prevents sensitization and alters acute and long-lasting effects of allergen-specific immunotherapy of murine allergic asthma
D. Russkamp, A. Aguilar-Pimentel, [...] C. B. Schmidt-Weber, S. Blank

 

February 2019, Cell Rep.
Blimp1 maintains regulatory T cell identity at sites of inflammation through epigenetic imprinting
G. Garg, A. Muschaweckh, [...] J. Huehn, A. Kallies, T. Korn

 

January 2019, Nat. Neuroscience
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
S. Parhizkar, T. Arzberger, [...] C. Haass

 

January 2019, Neural Plast. 
Immune Challenge Alters Reactivity of Hippocampal Noradrenergic System in Prenatally Stressed Aged Mice
G. Grigoryan, N. Lonnemann, M. Korte

 

November 2018, Prog Biophys Mol Biol.
PK/PD-based adaptive tailoring of oseltamivir doses to treat within-host influenza viral infections
G. Montaseri, A. Boianelli,  Hernandez-Vargas E.A., M. Meyer-Hermann 

 

November 2018, Brain Behav. Immun.
Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage
I. Waltl, C. Käufer, [...] U. Kalinke, W. Löscher

 

October 2018, Front. Cell. Neurosci.
IFN-g producing Th1 cells induce different transcriptional profiles in microglia and astrocytes
K. P. Chittappen, O. Dittrich-Breiholz, S.R. Talbot, P.A. Robert, J. Huehn, M. Stangel 

 

October 2018, Cell Rep.
Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Regulation during Viral Encephalitis
C. Chhatbar, C. N. Detje, [...] M. Stangel, U. Kalinke 

 

October 2018, Nat. Commun.
The olfactory epithelium as a port of entry in neonatal neurolisteriosis
D. Pägelow, C. Chhatbar, [...] U. Kalinke, [...] M. W. Hornef, M. Fulde 

 

September 2018, Front Immunol.
Computer Simulation of Multi-Color Brainbow Staining and Clonal Evolution of B Cells in Germinal Centers
M. Meyer-Hermann, C. Binder, L. Mesin, G.D. Victora

 

September 2018, PNAS
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures
C. Käufer, C. Chhatbar, [...] U. Kalinke, W. Löscher

 

August 2018, Plos Pathog.
Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice
W. Koestner, J. Spanier, [...] F. Wacker, U. Kalinke

 

July 2018, Nat. Med.
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
L. Bunse, S. Pusch, [...] W. Wick, M. Platten

 

April 2018, J. Hepatol.
Type I Interferon Receptor Signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis
K: Borst, T. Frenz, [...] M. Heikenwaelder, G. Sutter, U. Kalinke

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Funding period

Nov. 2017 – Dec. 2021

 

Funding amount

6,000,000 € from the Initiative and Networking Fund of the Helmholtz Association

5,587,127 € co-funding by the Research Centers

 

Participating Helmholtz Centers

German Cancer Research Center (DKFZ)
German Center for Neurodegenerative Diseases (DZNE)
Helmholtz Center Munich (HMGU)
Helmholtz Center for Infection Research (HZI)
Max Delbrück Center for Molecular Medicine (MDC)

 

Coordination

MDC

 

Governing Body

Klaus Rajewsky (MDC)
Michela Di Virgilio (MDC)
Matthias Heikenwälder (DKFZ)
Michael Heneka (DZNE)
Ulrich Kalinke (HZI)
Claudia Traidl-Hoffmann (HMGU)

 

Contact

 

Governing Body

Michela Di Virgilio
Michela.DiVirgilio@mdc-berlin.de

Klaus Rajewsky
Klaus.Rajewsky@mdc-berlin.de


Coordination

Charlotte Quirin
Charlotte.Quirin@mdc-berlin.de
+49 30 9406 1648

Nadja Oellrich
Nadja.Oellrich@mdc-berlin.de

 

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