The Beilhack Lab

A pioneering study published in Immunity today reveals how tissue-specific unconventional T cells travel via lymphatic pathways to lymph nodes, where they orchestrate customized immune responses. This breakthrough has profound implications for targeted vaccination and immunotherapy strategies.

Unconventional T cells, including invariant natural killer T cells, gamma delta T cells, and mucosal-associated invariant T cells, differ from conventional T cells by engaging in broader immune surveillance and responding to diverse signals, such as stress signals, lipid antigens, or metabolites.

“Our study demonstrates that local forces guide unconventional T cells from tissues to lymph nodes, where they imprint tissue-specific characteristics,” explains our collaboration partner Prof. Wolfgang Kastenmüller, who lead the international research team.” Dendritic cells have long been known to relay information from peripheral tissues to draining lymph nodes, initiating immune responses. However, it’s now evident that dendritic cells are not solely responsible for this crucial flow of information.  Each tissue harbors unique subtypes of unconventional T cells, influencing the composition and function of T cells in nearby lymph nodes.”

This diversity leads to varied immune responses within lymph nodes, where unconventional T cells form interconnected functional units across different T cell receptor-based lineages. These units are crucial for shaping both innate and adaptive immune responses tailored to the specific tissues drained by each lymph node.

Implications for Future Research and Medicine

Understanding how unconventional T cells migrate and function in lymph nodes is pivotal for advancing immunology and medical practice. Leveraging our insights allows scientists to enhance tissue-specific immune responses, paving the way for precision vaccination and immunotherapy approaches with reduced side effects. This progress holds promise for personalized medicine, facilitating more effective treatments that meet individual patient needs while minimizing adverse effects.

This interdisciplinary research project was led by Prof. Wolfgang Kastenmüller at Würzburg’s Institute for Systems Immunology at the Julius-Maximilians-University Würzburg, in collaboration with groups from the Würzburg Helmholtz Institute for RNA-based Infection Research (HIRI), the JMU Institute for Molecular Infection Biology (IMIB), the Centre d’Immunologie de Marseille-Luminy (CIML), and our team at the Department of Medicine II at Würzburg University Hospital. Financial support was provided by IZKF Würzburg, the German Research Foundation (DFG), the European Research Council (ERC), and the Max Planck Society.

For more information, visit the press release in German.

Publication Reference:

Ataide MA*, Knöpper K*, Cruz de Casas P*, Ugur M, Eickhoff S, Zou M, Shaikh H, Trivedi A, Grafen A, Yang T, Prinz I, Ohlsen K, Gomez de Agüero M, Beilhack A, Huehn J, Gaya M, Saliba AE, Gasteiger G, Kastenmüller W. (2022). Lymphatic migration of unconventional T cells promotes site-specific immunity in distinct lymph nodes. Immunity, 55(10):1813-1828.e9.

This research article was also highlighted in Immunity by Emily Thornton and Tal Arnon: “It takes a village to skew a lymph node.“

The running team of the Beilhack lab joined the Würzburg Marathon 2022. Alltogether 16 teams of the University Hospital participated in this sportive event to raise awareness and donations for cancer research.

In a landmark study Dr. Julia Dahlhoff published in the journal Leukemia  a groundbreaking approach to combat multiple myeloma (MM). The paper from our team, titled “Transient Regulatory T-Cell Targeting Triggers Immune Control of Multiple Myeloma and Prevents Disease Progression,” uncovers the potential of briefly depleting regulatory T-cells (Tregs) to unleash the body’s own immune system to eradicate this challenging blood cancer.

Multiple myeloma, characterized by the proliferation of malignant plasma cells in the bone marrow, often relapses due to the protective niche created by bone marrow-resident Tregs. The study reveals that Tregs not only cluster around malignant plasma cells but also support their survival and dissemination.

Using two syngeneic immunocompetent murine models, the team under the leadership of Prof. Andreas Beilhack demonstrated that temporary depletion of Tregs in mice with established MM led to a robust immune response, mediated by CD8 T cells and natural killer (NK) cells, resulting in complete and sustained remission of the disease.

“Targeting Tregs disrupts their suppressive grip on the immune system, allowing CD8 T cells and NK cells to attack and eliminate myeloma cells,” said Dr. Dahlhoff. “This short-term intervention effectively prevented MM progression and offers a new therapeutic strategy that minimizes the risk of autoimmunity.”

The study paves the way for developing Treg-targeted therapies, providing a novel avenue for treatment-resistant multiple myeloma.

Reference: 

Dahlhoff J, Manz H, Steinfatt T, Delgado-Tascon J, Seebacher E, Schneider T, Wilnit A, Mokhtari Z, Tabares P, Böckle D, Rasche L, Martin Kortüm K, Lutz MB, Einsele H, Brandl A, Beilhack A. (2022). Transient regulatory T cell targeting triggers immune control of multiple myeloma and prevents disease progression. Leukemia 36(3):790-800.

Former postdoctoral fellow and now young principal investigator at Bari University Dr. Antonio Solimando receives the IMS Young Investigator Award in Vienna, Austria.

Clinician-Scientist Dr. Antonio Solimando will present our award winning research project on cell adhesion-regulated epithelial-mesenchymal-transition resulting in extramedullary multiple myeloma disease manifestation at the 18^th International Myeloma Workshop in Vienna, Austria, on September 10^th, 2021. This is a wonderful reward for our continuing fruitful scientific collaboration on the mechanisms and new therapeutic targets in adhesion mediated cancer progression. In the past years the basic science of this research project has been generously supported by the DFG µbone consortium and the therapeutic research aspects by the Bayerische Forschungsstiftung.

Image courtesy: International Myeloma Society

 

The European Society of Blood and Marrow Transplantation awarded our research on the protective function of host intestinal macrophages in acute graft-versus-host disease with this year’s Basic Science Award.

At the EBMT presidential symposium on March 15, 2021, postdoctoral fellow Dr. Duc-Dung Le presented our work and received this prestigious award together with his co-first author Dr. Ana-Laura Jordán Garrote on behalf of our entire team at University Hospital Würzburg and our national and international collaboration partners. Many thanks go to all the enthusiastic team members and especially to our partners within the DFG Transregio 221 consortium on GvH and GvL for the excellent support!

Read more about this award here.

Watch the interview with postdoctoral fellow Dr. Duc Dung Le here or on Youtube here.

Clinical studies suggested that endothelial dysfunction and damage can be involved in the development and severity of acute graft-versus-host disease (aGvHD), a complication in patients undergoing allogeneic hematopoietic cell transplantation. In a new paper under the lead of Olaf Penack from the Charité Berlin we show extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Subsequently, therapeutic intervention with an already clinical approved endothelium-protecting agent improved outcome in a mouse model of steroid-refractory aGvHD.

Allogeneic hematopoietic stem transplantation (allo-HCT) is the only curative treatment option for many patients suffering from blood cancers. However, there are still risks for patients undergoing allo-HCT. One major complication is acute graft-versus-host disease (aGvHD) occuring in more than two thirds of patients. This inflammatory condition primarily affecting the skin, liver, and intestines. Although treatment with steroids is successful in most patients, about the 20%-25% of patients fail initial steroid treatment resulting in a very high mortality rate. Currently, no standard treatment for this steroid-refractory aGVHD is available and its pathobiology remains poorly understood, thereby hindering the development of novel therapeutic approaches.

The endothelium is the first contact for immunological effector cells in the blood and a key regulator in various inflammatory processes. The endothelium was shown to be relevant for early complications after allo-HCT such as transplantation-associated-microangiopathy, veno-occlusive disease, capillary leak syndrome and diffuse alveolar hemorrhage. Recent studies also suggested a critical role of the endothelium in aGvHD. Accordingly, we found increased percentage of apoptotic Casp3⁺ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. 

In mouse models of experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. Employing light-sheet fluorescence microscopy revealed structural changes in the colonic vasculature including increased vessel branching and vessel diameter. Human biopsies and murine tissues from steroid refractory aGvHD revealed extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent steroid refractory aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental steroid refractory aGvHD. The study by Steffen Cordes et al. demonstrates extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Consequently, therapeutic intervention by endothelium-protecting agents, such as sildenafil, appear attractive to treat steroid refractory aGvHD complementing current anti-inflammatory treatment options. 

 

This work resulted from a strong collaborative effort between clinicians and scientists from different European medical centers: The Charité Berlin and the University Hospitals of Barcelona (Spain), Hannover, Heidelberg and Würzburg. Our lab was supported for this study be the DFG collaborative research center TRR221 GvH-GvL (project B11).

 

Reference:

Cordes S, Mokhtari Z, Bartosova M, Mertlitz S, Riesner K, Shi Y, Mengwasser J, Kalupa M, McGeary A, Schleifenbaum J, Schrezenmeier J, Bullinger L, Diaz-Ricart M, Palomo M, Carrreras E, Beutel G, Schmitt CP, Beilhack A, Penack O. (2021). Endothelial damage and dysfunction in acute graft-versus-host disease. Haematologica 106(8):2147-2160.

Multiple myeloma is a malignant disease of antibody producing plasma cells. As this devastating type of cancer locates to the bones it seems that multiple myeloma highly depends on close interactions with the bone marrow microenvironment. In our new paper by clinician-scientist Dr. Antonio Solimando et al. we describe our new discovery that multiple myeloma cells use an adhesion molecule called JAM-A (Junctional-adhesion-molecule A) to interact with blood vessel lining endothelial cells. It appears as these endothelial-multiple myeloma interactions feed into a vicious cycle propagating disease progression.

Our projected started with our initial observation that the expression level of JAM-A by malignant plasma cells can predict disease outcome. Subsequently, we discovered that elevated membrane expression of JAM-A also on bone marrow endothelial cells of patients with newly diagnosed or relapsed-refractory multiple myeloma cells predicted poor clinical outcome.

Based on this finding we investigated how elevated JAM-A levels would contribute to more aggressive disease. We discovered that direct contact of endothelial cells with multiple myeloma cells would enhance JAM-A levels. Then it got even more interesting, as the cell adhesion molecule JAM-A has remarkable features: it can interact with itself if expressed on two opposing cell types. Furthermore, if JAM-A is shed by a cell, the soluble form of the JAM-A molecule can bind to cell-bound JAM-A, which in turn even enhances its binding capacity. What ensues is a vicious cycle of malignant plasma cells expressing and shedding JAM-A, increasing JAM-A expression on endothelial cells and stimulating blood vessel formation. In turn, increasing numbers of JAM-A-overexpressing endothelial cells can now better bind malignant plasma cells, which now find more interaction partners and by increasing the multiple myeloma niche space can produce more JAM-A. Consequently, using different experimental models we found that blocking the adhesion molecule JAM-A would inhibit blood vessel formation, reduce JAM-A interactions and impair multiple myeloma disease progression. These therapeutic effects of blocking JAM-A were observed in preclinical models not in patients and, therefore, must be interpreted with caution. Nevertheless, our new findings may point towards a potential Achilles’ heel of multiple myeloma that might be exploited therapeutically in the future.

This work was generally supported by the Bavarian Research Foundation within the research consortium FORTiTher and the German Research Council (DFG) consortium µbone.

Reference:

Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A. (2021). Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression. Haematologica 106(7):1943-1956.

In its current issue, the journal Nature Reviews Microbiology reports about our recent mBio research article advancing light-sheet fluorescence microscopy (LSFM) to study host-pathogen interactions within the 3D environment of the lung. In the news section Under the Lens, Manish S. Kushwah and Stephen Thorpe from Oxford University highlight our research article by former postdoctoral fellow Dr. Jorge Amich, postdoctoral fellow Zeinab Mokhtari et al. in their report A clearer picture of microbial biogeography.

Amich J*, Mokhtari Z*, Strobel M, Vialetto E, Sheta D, Yu Y, Hartweg J, Kalleda N, Jarick KJ, Brede C, Jordán-Garrote AL, Thusek S, Schmiedgen K, Arslan B, Pinnecker J, Thornton CR, Gunzer M, Krappmann S, Einsele H, Heinze KG, Beilhack A. (2020). 3D light sheet fluorescence microscopy of lungs to dissect local host immune – Aspergillus fumigatusinteractions. mBio 11(1): e02752-19

A new paper in Nature Communications by Brenner et al. demonstrates in mice and in human patients that cancer control strictly requires the activation of tumour-intrinsic, senescence-inducing cell cycle regulators by the immune system to stably arrest those cancer cells that escape from eradication.