A new study lead by Prof. Kai Hildner from Erlangen University identifies BATF-expressing T cells as key players in intestinal acute graft-versus-host disease (GvHD).
Alloreactive BATF+ effector memory T cells enhance inflammation by producing GM-CSF and augmenting the infiltration of innate immune cells in the intestinal mucosa. Zeng D, J Clin Invest 2018, © JCI.
Surprisingly, the transcription factor BATF controlled the formation of a distinct IL-7 receptor signaling–responsive GM-CSF+ T cell subset. These newly identified pathologic IL-7RhiGM-CSF+ T cells link IL-7, a cytokine previously mostly associated with T cell reconstitution, to the occurrence of acute GVHD. Furthermore, the study revealed GM-CSF derived from alloreactive T cells as a major driver of systemic and intestinal GvHD. These findings pinpoint the newly identified IL-7R/BATF/GM-CSF axis as a promising therapeutic target to prevent or even treat acute GvHD in patients undergoing allogeneic hematopoietic cell transplantation.
The new research article by Evelyn Ullrich et al. appeared today in the Journal of Clinical Investigation. The work resulted from a collaboration of an interdisciplinary team comprising several members of our newly founded DFG research consortium TR221 GvH-GvL between the partner universities Erlangen, Regensburg and Würzburg.
Commentary by Prof. Defu Zheng on this article in the Journal of Clinical Investigation.
Link to research article:
Ullrich E, Abendroth B, Rothamer J, Huber C, Büttner-Herold M, Buchele V, Vogler T, Longerich T, Zundler S, Völkl S, Beilhack A, Rose-John S, Wirtz S, Weber GF, Ghimire S, Kreutz M, Holler E, Mackensen A, Neurath MF, Hildner K. (2018). BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. J Clin Invest. 2018 Jan 29. pii: 89242. doi: 10.1172/JCI89242. [Epub ahead of print]
On January 23rd principal investigators gathered for the inaugural meeting of the new DFG TRR221 collaborative research center on the modulation of graft-versus-host and graft-versus-leukemia immune responses after allogeneic stem cell transplantation in Regensburg.
Allogeneic hematopoietic cell transplantation is a curative treatment regimen for many patients with leukemia and lymphoma. The new TRR221 consortium connects research teams from the universities of Erlangen, Regensburg and Würzburg to address key challenges of allogeneic hematopoietic cell transplantation. The efficacy of this therapy is mediated by the graft-versus-leukemia (GvL) effect by immune cells of the stem cell donor. However, this desired GvL does not occur to the same degree in all patients to prevent leukemia or lymphoma recurrence after allogeneic hematopoietic cell transplantation. Furthermore, the new forming immune system of the donor can attack healthy organ compartments of the stem cell recipients, an unwanted and often life-threatening immune reaction termed graft-versus-host disease (GvHD). Within the first five years after transplantation, about 60 percent of patients die from GVHD or leukemia.
Our new interdisciplinary research consortium aims to develop innovative immunomodulatory strategies for specifically enhancing the GvL effect and for selective attenuation of GvHD. Our most recent meeting in Regensburg provided the opportunity to elect the board of the consortium, to define the key priorities for the near future, and, importantly, to exchange our most recent research results. A great start for an exciting opportunity to tackle together an unsolved medical problem and to help patients through a concerted research effort.
A new paper in Science Immunology identified a molecule called BMP4 that plays a key role in the thymus’ extraordinary natural ability to recover from damage. Collaborating with scientists from the Memorial Sloan Kettering Hospital in New York City and the Fred Hutchinson Cancer Research Center in Seattle revealed how BMP4 and thymic endothelial cells enable thymus repair.
Thymic endothelial cells proved critical for thymic regeneration via their production of bone morphogenetic protein 4 (BMP4). Upon thymus damage, thymic endothelial cells increased their production of BMP4. Endothelial cell-derived BMP4 fostered development, maintenance, and regeneration of thymic epithelial cells. BMP4’s importance on endogenous tissue regeneration offers a potential clinical approach to enhance T cell immunity. Novel treatment regimens based on these findings may promote immune competence in patients undergoing chemo- and radiation therapy.
The Scientist: Researchers Develop a Technique to Regenerate the Mouse Thymus
Medical Press: How the immune system’s key organ regenerates itself
Wertheimer T, Velardi E, Tsai J, Cooper K, Xiao S, Kloss CC, Ottmüller KJ, Mokhtari Z, Brede C, deRoos P, Kinsella S, Palikuqi B, Ginsberg M, Young LF, Kreines F, Lieberman SR, Lazrak A, Guo P, Malard F, Smith OM, Shono Y, Jenq RR, Hanash AM, Nolan DJ, Butler JM, Beilhack A, Manley NR, Rafii S, Dudakov JA, van den Brink MRM. (2018). Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration. Sci Immunol 3:19.
In der Arbeitsgruppe für Experimentelle Stammzelltransplantation der Medizinischen Klinik und Poliklinik II des Universitätsklinikums Würzburg ist eine vorerst für ein Jahr befristete
ab Februar 2018 ganztags zu besetzen. Die Vergütung erfolgt nach TV-L.
Unsere wissenschaftliche Arbeitsgruppe beschäftigt sich mit der Frage, wie unser Immunsystem Krankheitserreger und Krebszellen finden und zerstören kann bzw. warum Immunzellen nach Stammzelltransplantation bestimmte Organe des Empfängers attackieren. Zur Beantwortung dieser Fragestellung führen wir Versuche mit lumineszierenden Mäusen, FACS Analyse, Immunfluoreszenzmikroskopie, Immunhistochemie und molekularbiologische Methoden, wie Klonieren, PCR und Real-time-PCR, durch. Unsere Arbeitsgruppe befindet sich in einem freundlichen, interdisziplinären Laborbereich und wir bieten die Möglichkeit in einer guten Arbeitsatmosphäre an einem sehr spannenden Forschungsprogramm aktiv mitzuwirken.
Gesucht sind engagierte, qualifizierte Bewerberinnen und Bewerber, die sich durch Teamgeist, Konzentrationsfähigkeit und Lernbereitschaft auszeichnen. Tierexperimentelle Kenntnisse sind wünschenswert, aber keine Voraussetzung. Bevorzugt werden motivierte Kanditatinnen und Kanditaten mit organisatorischen Fähigkeiten sowie Computer- und Englischkenntnissen.
Schwerbehinderte Bewerberinnen und Bewerber werden bei im Wesentlichen gleicher Eignung bevorzugt berücksichtigt.
Interessenten/-innen senden ihre elektronischen Bewerbungsunterlagen bis zum 19.01.2018 mit dem Kennwort
Bewerbung: MTA/BTA-Stelle an:
Prof. Dr. Dr. Andreas Beilhack
The DFG approves the new research consortium SFB TRR221, which focusses on harnessing anti-leukemia mechanisms without the risk of adverse immune reactions.
The new DFG consortium focuses on the modulation of transplant-versus-host and transplant-against-leukemia immune reactions.
Allogeneic hematopoietic stem cell transplantation is the only curative treatment option for many patients with leukemia and lymphoma. Their effectiveness is based on the so-called graft-versus-leukemia (GvL) effect: The transplanted immune cells of the donor form a new functional immune system in the patient to fight the tumor cells. However, the effect is not sufficient in all patients to prevent the return of leukemia or lymphoma. Furthermore, there is often an undesirable effect in which the immune cells of the donor attack healthy tissue of the patient, termed graft-versus-host disease (GvHD). Within the first five years after transplant, approximately 60 percent of patients die as a result of GvHD or the return of the disease.
A newly formed research consortium investigates how desired GvL responses can be separated from unwanted GvH reactions. The German Research Foundation (DFG) will fund the new SFB Transregio TRR221 consortium on the “Modulation of transplant-versus-host and transplant-against-leukemia immune reactions after allogeneic hematopoietic stem cell transplantation.” Under the leadership of Prof. Wolfgang Herr, three Bavarian universities – Erlangen, Regensburg and Würzburg will investigate the immunological mechanisms of blood stem cell transplantation. The teams of our consortium will address the central problems and deficits of allogeneic hematopoietic stem cell transplantation. Consequently we aim to develop immunomodulatory strategies for the specific enhancement of the GvL effect and for the selective attenuation of GvHD. This collective gain of knowledge will result in new treatment concepts. These will be tested outside the DFG TRR221 in clinical studies with the aim of reducing the incidence of morbidity and mortality of allogenic blood stem cell transplantation by promoting the highly effective GvL immune response without associated GvHD. The consortium is planned to operate for 12 years. On November 24, 2017, after a thorough two-step evaluation process, the DFG approved funding for an initial phase of four years.
With a generous donation, the married couple Merete and Alexander Knauf of the international building materials company of the same name are stimulating a promising basic research project in the Beilhack lab. Based on an entirely new approach, the project aims to control potential life-threatening immune reactions between a stem cell transplant and the recipient’s body.
From left: Prof. Andreas Beilhack and Musga Qureischi from the Experimental Stem Cell Transplantation Research Laboratory, the patrons Merete and Alexander Knauf, and Prof. Alfred Forchel, President of the University of Würzburg. © Arnika Hansen (Uniklinikum Würzburg).
“My wife and I are regularly involved in projects in which we have the impression that we can really help to advance important improvements in our society with financial support,” says Alexander Knauf, managing partner of the globally active building materials company Knauf from Iphofen near the city of Würzburg. Not least because his wife Merete is a medical doctor herself, this subject area is also in their common funding focus. In search of a suitable project, the patrons recently turned to Prof. Alfred Forchel. The President of the University of Würzburg presented them with a range of current local projects. Among them, the married couple Knauf chose a project of Prof. Beilhack with the aim to develop an entirely new immunotherapy concept. “We are talking here of basic research, but extremely goal-oriented and with high translational potential,” emphasizes the scientist Musga Qureischi, who is actively pursuing this project in the Beilhack lab. According to the young scientist, the new strategy specifically targets improvements in stem cell therapy, but if it succeeds, the principle could well be applied to many autoimmune and inflammatory diseases.
Private donation helps to prove effectiveness
“The generous donation of the couple Knauf helps to skip a typical hurdle in the German research funding landscape,” said University President Forchel, explaining: “For the acquisition of public funds, projects such as this must scientifically prove a high probability of success. But to be able to prove this, considerable resources are required. Private sponsors can help close this gap, as a kind of start-up financing. “
If the project goes well, this proof can be achieved within the next two years, according to Prof. Beilhack.
An adhesion molecule on multiple myeloma cells correlates with patient outcome and proves as a promising new target for cancer therapy. Today, the respected journal Leukemia published our new research article on JAM-A by lead authors Antonio Solimando and Andreas Brandl.
Our new study revealed that JAM-A expression correlates significantly with disease outcome in multiple myeloma patients. Targeting of JAM-A impacts cardinal features of cancer, such as multiple myeloma cell survival, progression and metastasis.
Read more about this new research publication.
Solimando AG*, Brandl A*, Mattenheimer K, Graf C, Ritz M, Ruckdeschel A, Stühmer T, Mokhtari Z, Rudelius M, Dotterweich J, Bittrich M, Desanti V, Ebert R, Trerotoli P, Frassanito MA, Rosenwald A, Vacca A, Einsele H, Jakob F, Beilhack A. (2017). JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia (advance online publication 24 October 2017) doi: 10.1038/leu.2017.287
*These authors contributed equally to this work.
The graduate college 3D Infect met for two days in Rothenburg ob der Tauber.
All the participating research teams of the DFG research training group 3D Infect joined for the second annual retreat. Graduate students and principal investigators of the graduate college actively participated to present and discuss the recent progress of the individual projects within the research training group. This vivid exchange and further input from visiting faculty, this year especially on pulmonary host-pathogen interactions, provided a fruitful basis to foster collaborations between the members of the RTG 3D Infect. One such collaborative project authored by the PhD student Sarah Schuster and members of the Engstler and Beilhack labs resulted already in a first joint-publication, which recently appeared in the distinguished journal eLife.
This year’s Workshop for Experimental Blood and Marrow Transplantation took place in Schweinfurt, a town on the river Main near Würzburg.
From September 19th to 20th, 2017 cellular immunotherapy, graft-versus-host disease and inflammation, tumor immunology and immune responses against infections were in the focus of 20 research lectures and seven poster presentations by young scientists from four different universities. This year’s meeting was hosted by the Beilhack lab. Three other active research groups joined from the Charité Berlin, and the Universities of Frankfurt and Freiburg. The Interdisciplinary Center for Clinical Research (IZKF) Würzburg generously supported this interdisciplinary young investigator meeting. Originally, this workshop had been inspired by the annual Stanford immunology retreats in Asilomar, California, which were always highlights for Robert Zeiser and Andreas Beilhack during their postdoctoral training at Stanford University. After returning to Europe the Zeiser and Beilhack labs initiated an annual two-day scientific workshop together with the young research labs of Evelyn Ullrich and Olaf Penack: Once a year these four research teams meet to discuss recent research progress and new perspectives in the field of hematopoietic cell transplantation and immunotherapy. Beside an intense scientific program there was also time for a brief visit to the Georg Schäfer Museum to enjoy Central European art from the 19th century. Already we are looking forward to our 10th workshop, which will be held near Frankfurt am Main in 2018.