Regenerative Immunology and Aging
Our work area is focusing on alterations of the immune system caused by the natural aging process, infections or diseases. We are interested in the cellular and molecular changes that cause the immune system to age. During aging, natural changes take place in the immune system making it vulnerable to infections or cancer and reducing vaccination efficiency. The mechanisms responsible for this reduced immunocompetence have not yet been identified - this is where our multidisciplinary research comes in. Our current and future projects focus primarily on clinical immunology, immune monitoring, immune-cell therapies and diagnostics.
Charité Corona Cross (CCC 2.0)
Structure and existing knowledge resulted in an early lead of the Charité in Germanys SARS-CoV-2 related research when the pandemics started in late 2019. We analyzed the anti-SARS-CoV-2 immunity in the first patients and healthy donors in winter 2020 and observed a spike-glycoprotein targeting T cell response in 32% of the healthy donors without prior exposure to SARS-CoV-2. Homology analysis revealed a potential cross-reactivity mediated by previous exposure to common corona cold viruses which we could validate in vitro (Braun et al., Nature, 2020). However, the impact on the population immunity remained unclear. Within Charité Corona Cross 2.0, we generated baseline values of >700 donors prior to infection and followed >20 individuals through their infection by monitoring cellular and humoral responses. Together with >30 closely monitored BioNTech/Pfizer vaccinated (uninfected) individuals the gathered data demonstrated that pre-existing immunity results in rapid humoral and cellular responses and higher IgG and neutralizing antibody titers upon virus clearance (Loyal et al., Science, 2021). While endemic corona cold virus specific immunity is widespread, anti-SARS-CoV-2 cross-immunity decreases with increasing age, potentially contributing to the higher susceptibility of elderly to severe disease. Since, follow up of cellular (cross)-immunity has been challenged by the strongly diversified infection (with different SARS-CoV-2 variants) and vaccination schedules. Antibody based classification into convalescents and/or vaccinated donors remained unreliable especially in asymptomatic infection. Utilizing different peptide pools, we try to dissect the different cohorts and monitor the development of cross-immunity during times of social distancing and masking (Loyal et al., in preparation).
Coronavirus surveillance (CCC 2.1)
We continuously screen several kindergartens in Berlin for cases of respiratory infections by collecting saliva samples from children, their parents and educators followed by qPCR and ELISA (IgA) analyses. SARS-Cov-2 positive participants were analyzed daily to examine the dynamic of virus load and antibody titers. The monitoring includes common corona cold viruses as well as other respiratory viruses (RSV, Flu) in order to observe potential co-dependencies in the infection dynamics.
Charité Corona Protect (CCP)
Initial vaccination strategies focused on the induction of high titers of (neutralizing) antibodies which can prevent the virus from entering the host cells or rapidly clear the virus from the body liquids. The limited antibody persistence and development of escape variants shifted the paradigm to an efficient induction of long-living memory T cell responses which can still efficiently protect against severe disease upon infection with highly mutated variants due to their broader epitope coverage. However, the characteristics of protection, especially in susceptible cohorts such as elderly and immunosuppressed, remain yet to be defined. Within Charite Corona Protect (CCP) we analyze the different open questions whether homo- or heterologous vaccination strategies provide a better immunity (Henze et al., Frontiers in Immunology, 2023), quality and longevity of immunity induced by infection or vaccination mediated boosters (Meyer-Arndt et al., in preparation) and the quality of (cross)-reactive immune responses in young versus old in the light of existing and potential arising variants of concern (Loyal et al., submitted).
CD8+ helper T cells
Activated CD4+ T cells transiently express CD40L and provide “help” in terms of APC licensing and/or the necessary stimuli for B cell maturation, somatic hypermutation and class switching. In contrast, CD8+ T cells are characterized as cytotoxic T cells, that can directly kill infected target cells. However, we previously identified a CD40L expressing CD8+ T cell population, which inherits the ability of DC licensing (Frentsch et al., Blood, 2013). In depth analysis revealed that CD8+ memory T cells have a CD4+ T cell alike diversity and can differentiate into Tc1, Tc2, Tc17, Tc17+1 and Tc22 subsets. Among them, the Tc2, Tc17 and Tc22 subsets lack cytotoxic features, express high levels of CD40L and resemble helper CD4+ T cells in their gene expression signature (Loyal et al., Nat. Comms., 2020). We could demonstrate that helper CD8+ T cells do not express the CD8 lineage transcription factor Runx3 which is in contrast present in cytotoxic CD4+ T cells and the cytotoxic cells can be distinguished from helper cells irrespective of their cell type by the expression of SLAMF7 (Loyal et al., Nat. Comms., 2020). In our current projects we are addressing the questions how these cells are induced and what is their role in human health and disease?
Peanut food allergy (KFO399)
Although the prevalence of IgE mediated food allergies is on the rise in most industrialized countries, it currently has no known cure and allergic patients are usually instructed to avoid food containing the allergens they are sensitized to. Our group is part of the food@ Clinical Research Unit (KFO 339), aiming to desensitize allergic donors using a liberated diet approach: the patients are instructed to regularly consume low doses of allergens below their individual reaction threshold for one year (as opposed to strict avoidance of the allergens), and various bio-samples are collected before and after the clinical intervention. In our group, we are focusing on the identification of immune mechanisms involved in food allergy sensitization and desensitization by monitoring the response to allergens of different immune cell subsets (T cells, B cells, antigen presenting cells, basophils). Our findings contribute to a better understanding of the immune circuits of food allergy and to refine laboratory diagnostic assays.
Thymus ultra-high content imaging
Myasthenia gravis (MG) is a T cell dependent autoimmune neuromuscular disease, where the normal communication between nerves and muscles through neurotransmitters is disrupted. Acetylcholine, a neurotransmitters secreted by nerve cells is unable to interact with receptor sites on the muscle cells at the nerve-muscle junction, due to antibodies produced by the immune system that block or destroy these receptor sites. Antibodies can also block the function of other proteins, such as muscle-specific receptor tyrosine kinase (MuSK) or lipoprotein-related protein 4 (LRP4) that can also result in the development of this condition.
The thymus is a lymphoid organ that is located at the upper front region of the chest, beneath the sternum, and in front of the heart. The thymus consists of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule. The thymus is the largest during neonatal and pre-adolescent periods, gradually decreasing in size and activity from the early teens. T cells mature in the thymus and are an important part of the adaptive immune system. Abnormalities in the thymus, such as thymoma or hyperplasia is observed in patients with MG. Self-reactive T cells directed against muscle antigens are detected in MG patients. Therefore, thymectomy is often performed to reduce MG related symptoms.
Our project focuses on imaging healthy thymus and diseased thymus from MG patients by utilizing a high content imaging platform (MACSima™) that can analyse hundreds of markers on a single sample. The objective is to have a better understanding of the histology and expression of important markers in healthy and diseased thymus and to gain insights into the pathogenic role of the thymus in MG.
Efficacy of immune checkpoint inhibitor treatment in melanoma
Over the last decade immune-checkpoint inhibitors (ICI) immunotherapy has shown promise as a treatment for melanoma skin cancer. However, ICI treatment has been limited to 40-60% response rate in patients and associated with several immune-related adverse events. This calls for the development of a prediction tool that can identify patients with greater chance of benefiting this immunotherapy. Human-relevant testing platforms can potentially better predict human response in clinical studies and present an attractive alternative for animal testing platform in research. In this project we aim to achieve an immune competent human skin-on-a-chip testing platform, used as a personalized prediction tool for ICI effect on patients prior to treatment. This platform will include skin-on-a-chip model with circulating T cells composed of autologous cells isolated from patient’s skin biopsies and blood samples. Establishing such platform can potentially prevent unnecessary ICI immunotherapy in non-responsive melanoma patients and will allow further investigation of T cell activation and function in human skin.