Paul-Ehrlich-Institut

Information on the Use of Cookies

In order to operate and optimise our website, we would like to collect and analyse statistical information completely anonymously. Will you accept the temporary use of statistics cookies?

You can revoke your consent at any time in our privacy policy.

OK

Im­munol­o­gy Re­search Group

Immunology: Infection by Leishmania (Source: Paul-Ehrlich-Institut)

The Immunology Division is responsible for marketing authorisation and batch release of immunotherapeutics such as antibodies, immunoglobulins, or antisera. Research projects of the Research Immunology Section make an important contribution to our expertise to guarantee a high quality evaluation of novel biomedical strategies and innovative experimental approaches in a wide range of immunological fields.

Research Focus

One research focus is the investigation of the effect of adjuvants on human immune cells. Adjuvants are added to vaccines as so-called drug boosters where the antigen alone triggers only a moderate or insufficient immune response. Results of this research contribute to a better understanding of the function of adjuvants and support us in the evaluation of new vaccines during the approval process. Another focus is the analysis of strategies used by pathogens to circumvent the immune defense and prevent their detection by the immune system. As a model of an intracellular pathogen infecting human immune cells, we work with Leishmania, the pathogen causing the tropical disease leishmaniasis, and primary lymphocytes derived from human blood.

In addition, we investigate mechanisms of T cell repertoire formation (i.e. T cell diversity) and its maintenance in the organism (homeostasis). Here, comparisons are made between T cell populations that originate from different organs, derive from different individuals, or are isolated after experimental changes. These comparisons allow conclusions to be drawn about the mechanisms that influence the T cell repertoire and that determine whether and what type of immune response can be triggered.

Another research focus is the investigation of severe side effects of biomedicines such as monoclonal antibodies or blood coagulation products. We analyse the underlying molecular and cellular immunological mechanisms of these adverse effects, looking at both innate and adaptive immune responses. In addition, we aim to develop predictive in vitro assay systems capable of reliably mapping known side effects of this group of drugs, such as the formation of so-called anti-drug-antibodies (ADA) or vascular leakage syndrome (VL), i.e. the pathological permeability of the vasculature.

Where appropriate, we bring our long-standing expertise with a wide variety of viral infections as model pathogens or model antigens to bear on the topic of side effects of biopharmaceutical or immunological drugs described above.

Research Projects

Immunomodulatory effects of adjuvants/strategies of Leishmania to circumvent immune defenses

Adjuvants are added to many vaccines as boosters to elicit a directed immune response against the antigen. Each adjuvant has a specific mode of action for this purpose, which affects the efficacy of the vaccine. For human primary immune cells, we have developed a model to compare the immunomodulatory effects of adjuvants on cells of the innate and adaptive immune system. The findings on the individual immune signatures of adjuvants contribute to a better understanding of their function and assist us in the evaluation of new vaccines during the regulatory process.

We examine the effect of an adjuvant on the activation of innate immune cells (e.g. dendritic cells) and adaptive immune cells (e.g. T, B, and NK cells).  Different adjuvants stimulate immune cells in a specific way and with varying strength. We examine the effect of an adjuvant on the activation of innate immune cells (e.g. dendritic cells) and adaptive immune cells (e.g. T, B, and NK cells). Different adjuvants stimulate immune cells in a specific way and with varying strength. Source: Paul-Ehrlich-Institut (created with BioRender.com)

Furthermore, we analyse strategies of pathogens to circumvent the human immune defense and to prevent their own detection by the immune system. For this purpose, we work with the obligate intracellular parasites Leishmania, which can cause the tropical disease leishmaniasis. Depending on the pathogen type, these pathogens cause cutaneous, self-healing leishmaniasis, or a more severe form of the disease, visceral leishmaniasis. In a mainly third-party funded project (Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz; LOEWE), we identify genes or proteins of the parasites that are potential drug targets or can be used to develop a vaccine against Leishmania. Specifically, we apply CRISPR/Cas9-mediated deletions of parasites genome to identify genes or proteins that have a function in survival or replication of these parasites in human host cells.

To this end, we perform infection experiments with primary human host cells of the innate immune system, in particular macrophages. In the macrophage-like transdifferentiated BLaER1 cell line, we can study their function in detail by genetically modifying receptors and resistance factors on a molecular level. In addition, we study the effects of Leishmania infection on the adaptive immune system, particularly on T cells. Another important aspect for infection progression is the transmission and spreading of Leishmania to new host cells. Within the framework of a DFG-funded Priority Programme, we work to find out the mechanisms by which Leishmania exit their old host cells and how they are taken up into the new host cells.

Furthermore, we use this human infection model to examine the functionality of various already marketed immunomodulatory antibodies, such as anti-TNF-alpha (tumor-necrosis-factor alpha) involved in inflammatory processes or immune activation. The functionality of so-called checkpoint inhibitors, for example PD-1 inhibitors, which lead to an increase in the activity of the immune system against tumor tissue, can also be studied in the infection model.

After uptake of Leishmania promastigotes into phagocytes, parasites develop into the replicative amastigote form that can lead to disease development. After uptake of Leishmania promastigotes into phagocytes, parasites develop into the replicative amastigote form that can lead to disease development. Pro-inflammatory cytokines and chemokines released from infected phagocytes can activate further immune cells (e.g. DC, T, B, and NK cells), helping to clear the infection and leading to disease control. Source: Paul-Ehrlich-Institut (created with BioRender.com)

For the investigation of molecular changes in host cells and adaptive immune cells as a consequence of infection, we use various methods based on flow cytometry. In addition to various cellular and molecular biological methods, we apply state-of-the-art imaging techniques of confocal and live cell microscopy. Combining this approach with electron microscopic analysis of the primary ultrastructure of human host cells enables us to understand how intracellular Leishmania interact with their host cells and inhibit an effective immune response.

Responsible for the Research Project

Professor Dr Ger van Zandbergen
Publications
Email: Ger.vanZandbergen@pei.de

Immunological basics/T cell development

Another project deals with mechanisms of the formation of a T cell repertoire (i.e. the diversity of T cells) and its maintenance in the organism (homeostasis). For this purpose, the T cell repertoire of T cell populations to be investigated, such as helper or killer T cells, is recorded by means of next-generation sequencing (NGS). In collaboration with partners performing bioinformatic analyses, this allows comparison of T cell populations that originate from different organs, derived from different individuals, or are isolated following different experimental modifications. These comparisons allow conclusions to be drawn about the mechanisms that influence the T cell repertoire and that determine whether and what type of immune response can be triggered. The group also uses techniques (e.g. ‘gnotobiotics’) to determine the influence of germs of the natural gut flora (microbiome) on the T cell repertoire by different experimental colonisations with naturally occurring germs.

In particular, the research group is interested in the ways in which T cells compete with each other in maintaining the T cell repertoire. In the past it has been shown that T cells compete for their 'homeostatic expansion'. This was the case even when T cells differed in MHC restriction determined by the particular T cell receptor. Ultimately, the 'degree of competitiveness' was determined by the T cell receptor. Interestingly, however, T cells carrying a more 'advantageous' T cell receptor do not regularly predominate. Why this does not happen is not yet clear, but it does result in the maintenance of diversity in the T cell repertoire. A high diversity of the T cell repertoire is essential for the organism so that the immune system can always tackle new (disease) pathogens.

Fortunately, the processes for maintaining T cell diversity usually work flawlessly, but we now know that, for example, the repertoire of T cells can decrease as the organism ages. This leads to impairments, because an immune response against a new pathogen may then hardly occur or only to a limited extent.

Responsible for the Research Project

Dr Jörg Kirberg
Publications
Email: Joerg.Kirberg@pei.de

Severe side effects of biopharmaceutical or immunological drugs

Hemophilia A (HA) is a severe blood coagulation disorder in which the coagulation factor (F)VIII is not produced at all or only to a very limited extent or in an altered form by the patient. HA patients are usually treated with recombinant or plasmatic FVIII products as part of a substitution therapy. However, about 25-35% of patients with severe disease develop ADA, which can severely limit or completely render treatment with therapeutic FVIII ineffective. In our research, we aim to address the question of why only some HA patients develop ADA while others do not. How do cells of innate immunity contribute to the development of ADA or to the immunogenicity of FVIII products and what is the role of immunological danger signals?

Up to now, it is not entirely clear, why some FVIII-treated patients develop ADA while others do not. Up to now, it is not entirely clear, why some FVIII-treated patients develop ADA while others do not. Source: Paul-Ehrlich-Institut (created with BioRender.com)

The EU consortium imSAVAR (Immune Safety Avatar; nonclinical mimicking of the immune system effects of immunomodulatory therapies) has set itself the goal of developing new concepts for testing immunomodulatory therapies. The focus is on the improvement of existing and the development of new model systems, e.g. in order to better mirror and thus predict severe side effects of biopharmaceutical drugs. As a partner of this consortium we would like to answer the following questions: How do immune cells contribute to the formation of VL? How do immune cells interact with endothelial cells in this process? How can we mirror VL in vitro? How can we develop an in vitro assay system to predict VL induced by biomedicines?

Vascular leakage is a severe and life-threatening effect induced by a number of (immunological) settings including the treatment with biopharmaceutical medicines. Vascular leakage is a severe and life-threatening effect induced by a number of (immunological) settings including the treatment with biopharmaceutical medicines. Source: Paul-Ehrlich-Institut (created with BioRender.com)

Immunobiology of viral infections

For many years the research group has also been dealing with viral infections in the human and murine system. Where appropriate, we bring this long-standing expertise with a wide variety of viral infections as model pathogens or model antigens into the topic of side effects of biopharmaceutical or immunological drugs described above.

Responsible for the Research Project

Professor Dr. Zoe Waibler
Publications
Email: Zoe.Waibler@pei.de

Research Group Head

Professor Dr Ger van Zandbergen
Publications
Email: Ger.vanZandbergen@pei.de

Deputy Research Group Head

Professor Dr Zoe Waibler
Publications
Email: Zoe.Waibler@pei.de

Updated: 04.08.2023