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Projects

The scientific research is structurally divided into two project areas:

Project area A: Strengthening GvL effects

Project area B: Prevention and treatment of GvHD.

This division has proven to be successful and constructive. Collaborative activities between the project areas have transformed the TRR 221 into a tight network in which it is clearly recognized that each GvL-modulating strategy must take into account its influence on GvHD (and vice versa). 

What are A-Projects?

Research projects that focus on the amplification of the graft-versus-leukemia (GvL) effect are grouped as A-projects. Briefly, they explore T cell redirection tools (i.e. T cell receptors (TCRs; A01), chimeric antigen receptors (CARs; A02, A03), tri-specific antibodies (A04) for the enhancement of hematopoiesis-restricted GvL activity and examine the reactivation of silenced GvL responses through improved functional and reproductive “fitness” of donor immune cells. The latter approaches include the amelioration of metabolic stress (A06), the transfer of T memory stem cells (A07) and the co-activation of innate nucleic acid receptor pathways (A08).

Whats is Project B

Prevention and treatment of GvHD by targeting cell signaling and metabolic pathways, by strengthening immune regulatory networks and by modulating GvHD-promoting co- factors The B-projects focus on the investigation of cell signaling and metabolic pathways (B02-04, B12, B14), immune regulatory/suppressive cells and networks in acute and chronic GvHD (B01, B07- B10, B15) and GvHD-promoting co-factors (B11-B13, B15). Based on their pathophysiological findings, they aim to develop and/or advance novel immunomodulatory strategies for effective prophylaxis and therapy of severe GvHD.  

Taken together, the B-projects tackle the GvHD problem from different angles with the aim to jointly develop innovative complementary or synergistic strategies. The coordinated time- and event-driven biopsy program on gut GvHD in Regensburg provides several B-projects with clinical samples and data of patients for research analyses. All PIs have proven unrestricted willingness to share their expertise, models, technologies and reagents with all other investigators. Promising strategies in GvL projects have been evaluated with respect to their influence on GvHD by the cooperating partners (and vice versa) and all participating institutions supported translational studies evolving from the TRR 221 projects (e.g. B01, B07, B10, B13, MAGIC trial).

Whats is Service Project

Information Infrastructure Project (INF), Service Projects (Z), and Integrated Research Training Group (IRTG) The A/B projects have been strongly supported by the newly established INF project (T. Dandekar, E. Holler, B. Kehr, M. Kunz) that provides the data infrastructure backbone, supporting large-scale omics, imaging, and clinical data. The INF PIs have developed a bioinformatics and data management platform, enabling mechanistic insights into GvHD and GvL immune responses and supporting translational and educational activities. Their broad and diverse expert knowledge was invaluable and contributed significantly to several TRR 221 publications (e.g., INF, refs. 1,10,23). As an outstanding INF achievement the clinical data integration system (DIS) BITCARE has been established at all three sites. Indispensable service was also provided by the pathology project Z01 (M. B¸ttner-Herold, M. Evert, A. Rosenwald), that performs the coordinated sampling and processing of human and murine tissues at each site and employs standardized consensus diagnosis and grading of experimental and human GvHD. The latter has been clearly improved by the TRR 221 owned virtual pathology platform and online CaseCentre (Sysmex/HP), that are both used to jointly evaluate digitized GvHD cases across sites. The project leaders conducted a Round Robin test on human colonic GvHD biopsies to ensure harmonization of the diagnostic approach by the involved pathologists (Z01, ref. 1). A variety of tissue-based histochemical, immunohistochemical, ultrastructural and molecular methods were performed as requested by TRR 221 projects (e.g., refs. 6,7). Service project Z02 by P. Hoffmann, T. Winkler, and A. Beilhack supports the A/B-projects by the generation and cross-breeding of numerous genetically modified mouse strains (e.g. loxP flank in Klf6 gene for conditional deleter mice, IL3 & Csf2 knockout mice, and novel split-cre mice for specific deletion of target genes by a combinatorial expression of the cre recombinase) and assists the projects on-site in the performance of complex mouse ASCT experiments and the conduction of sophisticated in vivo and ex vivo imaging studies. To study the role of the intestinal microbiome in ASCT, Z02 utilizes the proprietary germfree (GF) mouse facility in Regensburg and has performed several ASCT experiments investigating the course of GvHD under GF conditions in coop with B07, B03, B09, and B12. Moreover, a central human biomaterial repository supported by Z03 funds collected samples from hematologic neoplasias, which were provided to A/B-projects as required. To advance ASCT, talented early career researchers (ECRs) require training in their specific field as well as in the basic biology and clinical problems of ASCT. For this purpose, PIs M. Edinger, A. Kremer and F. Berberich-Siebelt further developed and strengthened the cross-site IRTG for doctoral students (PhD, MD) and for MDs (Dr. med.). All IRTG students are enrolled in local graduate programs and the IRTG focuses on complementary ASCT training modules detailed in the IRTG chapter. The joined training of doctoral candidates in medicine (Dr. med.) and natural sciences (Dr. rer. nat./PhD) as well as human biology (Dr. rer. biol. hum./Dr. rer. physiol.) has fostered the 14General information interdisciplinary cooperation and exchange of ideas between scientists and physicians to bridge the gap between laboratory and clinical research. During the 2nd FP, TRR 221 project leaders published 139 peer-reviewed publications on TRR specific topics (w/o reviews and clinical studies; only first and last authorships counted), of which 81 publications list project leaders of at least two different TRR projects as authors (evaluation period: 01/2022 to 04/2025; see also Fig. 3, cooperation array). Of these joint publications, 23 include project leaders from two and 9 from three TRR sites, respectively. Many more joint manuscripts are currently submitted for publication or are in preparation. Notably, joint publications (i.e., from at least two different projects) in the 1st FP (evaluation period: 01/2018 to 07/2021) were 74, of which 12 included project leaders from two and 3 from three TRR 221 sites (as detailed in our last proposal). This strong increase of joint cross-site publications from the 1st to 2nd FP clearly demonstrates that the TRR 221 has evolved into a strongly interacting and intensely collaborating research consortium during the first two FPs.

Project B02

Targeting of TNFR2 and related molecules to separate graft-versus-host disease (GvHD) from the GvL effect
Site: Würzburg
Principal Investigator: Prof. Dr. rer. nat. Harald Wajant , Dr. rer. nat. Isabell Lang

We developed two novel human (hu) TNFR2 agonists with high specific activity and excellent stability and productivity: i) a nanobody-based agonist showing anti-GvHD activity in huTNFR2 knockin (ki) mice and ii) a huTNFR2-specific huTNF-based agonist whose murine surrogate exerts anti-GvHD activity in wild type mice. The two human agonists will now be compared head-to-head in huTNFR2 ki mice with regard to their anti-GvHD- and GvHD/GvL-separating activity to identify the lead candidate for clinical translation.

 

  1. Siegmund D, Wajant H. TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond. Nat Rev Rheumatol 2023;19(9):576-91. doi: 10.1038/s41584-023-01002-7.
  2. Prada JP, Wangorsch G, Kucka K, Lang I, Dandekar T, Wajant H. A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2. Bioinformatics 2021;37(5):669-76. doi: 10.1093/bioinformatics/btaa844.
  3. Kucka K, Lang I, Zhang T, Siegmund D, Medler J, Wajant H. Membrane lymphotoxin-α(2)β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist. Cell Death Dis 2021;12(4):360. doi: 10.1038/s41419-021-03633-8.
  4. Lang I, Füllsack S, Wajant H. Lack of Evidence for a Direct Interaction of Progranulin and Tumor Necrosis Factor Receptor-1 and Tumor Necrosis Factor Receptor-2 From Cellular Binding Studies. Front Immunol 2018;9:793. doi: 10.3389/fimmu.2018.00793.
  5. Medler J, Nelke J, Weisenberger D, Steinfatt T, Rothaug M, Berr S, Hünig T, Beilhack A, Wajant H. TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity. Cell Death Dis 2019;10(3):224. doi: 10.1038/s41419-019-1456-x.
  6. Vargas JG, Wagner J, Shaikh H, Lang I, Medler J, Anany M, Steinfatt T, Mosca JP, Haack S, Dahlhoff J, Büttner-Herold M, Graf C, Viera EA, Einsele H, Wajant H*, Beilhack A*. A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity. Front Immunol 2022;13:888274. doi: 10.3389/fimmu.2022.888274.
  7. Anany MA, Haack S, Lang I, Dahlhoff J, Vargas JG, Steinfatt T, Päckert L, Weisenberger D, Zaitseva O, Medler J, Kucka K, Zhang T, Van Belle T, van Rompaey L, Beilhack A, Wajant H. Generic design principles for antibody-based tumour necrosis factor (TNF) receptor 2 (TNFR2) agonists with FcγR-independent agonism. Theranostics 2024;14(2):496-509. doi: 10.7150/thno.84404.
  8. Medler J, Kucka K, Melo V, Zhang T, von Rotenhan S, Ulrich J, Bremer E, Hudecek M, Beilhack A, Wajant H. CD40- and 41BB-specific antibody fusion proteins with PDL1 blockade-restricted agonism. Theranostics 2022;12(4):1486-99. doi: 10.7150/thno.66119.
  9. Zaitseva O, Anany M, Wajant H*, Lang I*. Basic characterization of antibodies targeting receptors of the tumor necrosis factor receptor superfamily. Front Immunol 2023;14:1115667. doi: 10.3389/fimmu.2023.1115667.
  10. Hesen N, Anany M, Freidel A, Baker M, Siegmund D, Zaitseva O, Wajant H, Lang I. Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism. Bioengineered 2024.15(1);2302246. doi: 10.1080/21655979.2024.2302246.
  • Prof. Dr. rer. nat. Harald Wajant
    University Hospital Würzburg
    Department of Medicine II
    Molecular Internal Medicine
    Röntgenring 11
    97070 Würzburg
    T: +49 931 201-71000
    harald.wajant@mail-uni-wuerzburg.de
  • Dr. rer. nat. Isabell Lang
    University Hospital Würzburg
    Department of Internal Medicine II
    Division of Molecular Internal Medicine
    Auverahaus, Grombühlstraße 12
    97080 Würzburg
    T: +49 931 201-71040
    Lang_I@ukw.de

 

Project B03

Generation, molecular characteristics and effector mechanisms of CSF2+ T cells in GvHD
Site: Erlangen
Principal Investigator: Prof. Dr. med. Kai Hildner, Prof. Dr. Krystelle Nganou-Makamdop, PhD

Based on our preliminary work we hypothesize that distinct microbial signatures foster a subtle immunological milieu shift thereby promoting CSF2+ T cell-mediated GvHD. To test this systematically, we link immune, microbial and clinical profiles of CSF2-driven intestinal pathology in preclinical models. Moreover, we perform in depth characterizations of blood and gut CSF-2+ T cells in ASCT patients to explore the mechanisms of T cell differentiation. Lastly, our microbiome analysis seeks to identify drivers of CSF2 in ASCT patients. Overall, we aim to identify key mechanisms underlying CSF2+ T cell driven GvHD.

 

  1. Thiagarajan S, Neurath MF, Hildner K. Resolution of acute intestinal graft-versus-host disease. Semin Immunopathol 2019;41(6):655-64. doi: 10.1007/s00281-019-00769-w. 
  2. 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. BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. J Clin Invest 2018;128(3):916-30. doi: 10.1172/JCI89242. 
  3. Buchele V, Abendroth B, Büttner-Herold M, Vogler T, Rothamer J, Ghimire S, Ullrich E, Holler E, Neurath MF, Hildner K. Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis. Front Immunol 2018;9:1138. doi: 10.3389/fimmu.2018.01138. 
  4. Enderle K, Dinkel M, Spath EM, Schmid B, Zundler S, Tripal P, Neurath MF, Hildner K*, Neufert C*. Dynamic Imaging of IEL-IEC Co-Cultures Allows for Quantification of CD103-Dependent T Cell Migration. Int J Mol Sci 2021;22(10).: 5148. doi: 10.3390/ijms22105148.*shared senior authorship 
  5. Matthe DM, Dinkel M, Schmid B, Vogler T, Neurath MF, Poeck H, Neufert C, Büttner-Herold M, Hildner K. Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease. Front Immunol 2023;14:1253514. doi: 10.3389/fimmu.2023.1253514. 
  6. Buchele V, Konein P, Vogler T, Kunert T, Enderle K, Khan H, Büttner-Herold M, Lehmann CHK, Amon L, Wirtz S, Dudziak D, Neurath MF, Neufert C, Hildner K. Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner. Front Immunol 2020;11:590893. doi: 10.3389/fimmu.2020.590893. 
  7. Nganou-Makamdop K, Douek DC. The Gut and the Translocated Microbiomes in HIV Infection: Current Concepts and Future Avenues. Pathog Immun 2024;9(1):168-94. doi: 10.20411/pai.v9i1.693. 
  8. Morou A, Brunet-Ratnasingham E, Dube M, Charlebois R, Mercier E, Darko S, Brassard N, Nganou-Makamdop K, Arumugam S, Gendron-Lepage G, Yang L, Niessl J, Baxter AE, Billingsley JM, Rajakumar PA, Lefebvre F, Johnson RP, Tremblay C, Routy JP, Wyatt RT, Finzi A, Douek DC, Kaufmann DE. Altered differentiation is central to HIV-specific CD4+ T cell dysfunction in progressive disease. Nat Immunol 2019;20(8):1059-70. doi: 10.1038/s41590-019-0418-x. 
  9. Nganou-Makamdop K*, Talla A*, Sharma AA*, Darko S, Ransier A, Laboune F, Chipman JG, Beilman GJ, Hoskuldsson T, Fourati S, Schmidt TE, Arumugam S, Lima NS, Moon D, Callisto S, Schoephoerster J, Tomalka J, Mugyenyi P, Ssali F, Muloma P, Ssengendo P, Leda AR, Cheu RK, Flynn JK, Morou A, Brunet-Ratnasingham E, Rodriguez B, Lederman MM, Kaufmann DE, Klatt NR, Kityo C, Brenchley JM, Schacker TW, Sekaly RP, Douek DC. Translocated microbiome composition determines immunological outcome in treated HIV infection. Cell 2021;184(15):3899-914 e16. doi: 10.1016/j.cell.2021.05.023. 
  10. Kiessling M, Cole JJ, Kübel S, Klein P, Korn K, Henry AR, Laboune F, Fourati S, Harrer E, Harrer T, Douek DC, Überla K, Nganou-Makamdop K. Chronic inflammation degrades CD4 T cell immunity to prior vaccines in treated HIV infection. Nat Commun 2024;15(1):10200. doi: 10.1038/s41467-024-54605-3. 
  • Prof. Dr. med. Kai Hildner
    University Hospital Erlangen
    Department of Medicine 1
    Ulmenweg 18
    91054 Erlangen
    T: +49 9131 85-35000 o. 85-45173
    kai.hildner@uk-erlangen.de

Project B07

GvHD therapy with donor regulatory T cells
Site: Regensburg
Principal Investigators: PD Dr. rer. nat. Petra Hoffmann, Prof. Dr. rer. nat. Michael Rehli, Prof. Dr. med. Matthias Edinger

We initially demonstrated that donor CD4+CD25+Foxp3+ regulatory T cells (Treg) prevent acute GvHD after MHC-mismatched ASCT. We then showed that they are also efficacious in the treatment of aGvHD and revealed that donor Treg rapidly adapt their phenotype and gene expression to the local environment, especially in the gastrointestinal tract. We now explore whether the microbiome contributes to organ-specific Treg adaptation, examine the mechanisms underlying their immune and tissue regenerating effects and determine, whether their therapeutic efficacy can be enhanced by targeting tissue-specific or ubiquitous antigens.

 

 

  1. Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity 2021;54(4):702-20 e17. DOI: 10.1016/j.immuni.2021.03.007.
  2. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002;196(3):389-99. DOI: 10.1084/jem.20020399.
  3. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003;9(9):1144-50. DOI: 10.1038/nm915.
  4. Riegel C, Boeld TJ, Doser K, Huber E, Hoffmann P*, Edinger M*. Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells. Leukemia 2020;34(3):895-908. DOI: 10.1038/s41375-019-0625-3.
  5. Dittmar DJ*, Pielmeier F*, Strieder N, Fischer A, Herbst M, Stanewsky H, Wenzl N, Röseler E, Eder R, Gebhard C, Schwarzfischer-Pfeilschifter L, Albrecht C, Herr W, Edinger M*, Hoffmann P*, Rehli M*. Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease. Nat Commun 2024;15(1):3224. DOI: 10.1038/s41467-024-47575-z.
  6. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, Edinger M. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006;108(13):4260-7. DOI: 10.1182/blood-2006-06-027409.
  7. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 2004;104(3):895-903. DOI: 10.1182/blood-2004-01-0086.
  8. Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B, Dada A, Niemand C, Assenmacher M, Orsó E, Andreesen R, Holler E, Edinger M. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant 2006;12(3):267-74. DOI: 10.1016/j.bbmt.2006.01.005.
  9. Schmidl C, Hansmann L, Lassmann T, Balwierz PJ, Kawaji H, Itoh M, Kawai J, Nagao-Sato S, Suzuki H, Andreesen R, Hayashizaki Y, Forrest AR, Carninci P, Hoffmann P, Edinger M, Rehli M, consortium F. The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 2014;123(17):e68-78. DOI: 10.1182/blood-2013-02-486944.
  10. Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009;19(7):1165-74. DOI: 10.1101/gr.091470.109.
  • PD Dr. rer. nat. Petra Hoffmann
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38492
    petra.hoffmann(at)ukr.de
  • Prof. Dr. rer. nat. Michael Rehli
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38487
    michael.rehli(at)ukr.de
  • Prof. Dr. med. Matthias Edinger
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5582
    matthias.edinger(at)ukr.de

Project B08

Harnessing tissue homeostasis-promoting functions of specialized regulatory T cells in graft-versus-host disease.
Site: Regensburg, Erlangen-Nürnberg
Principal Investigator: Prof. Dr. med. Markus Feuerer Prof., Dr. Frederik Graw PhD

Regulatory T cells (Treg) perform two distinct functions: they maintain self-tolerance and support organ homeostasis by differentiation into specialized tissue Treg cells. We aim to harness the tissue-repair, organ-homeostasis promoting function of tissue-resident Treg cells to prevent or treat graft-versus-host disease after allogeneic bone marrow transplantation. In this respect, we study a TH2-biased tissue Treg population that is present in virtually all organs. We will use loss-of-function and gain-of-function experiments to understand how these cells function during GvHD. Finally, we want to translate these findings into the human context.

 

  1. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D.  Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15(8):930-9. doi: 10.1038/nm.2002.
  2. Delacher M, Imbusch CD, Weichenhan D, Breiling A, Hotz-Wagenblatt A, Träger U, Hofer AC, Kägebein D, Wang Q, Frauhammer F, Mallm JP, Bauer K, Herrmann C, Lang PA, Brors B, Plass C, Feuerer M. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat Immunol 2017;18(10):1160-72. doi: 10.1038/ni.3799.
  3. Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C, Feuerer M. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity 2020;52(2):295-312.e11. doi: 10.1016/j.immuni.2019.12.002. 
  4. Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity 2021;54(4):702-20.e17. doi: 10.1016/j.immuni.2021.03.007.
  5. Delacher M, Schmidleithner L, Simon M, Stüve P, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Ruhland B, Hofmann V, Bittner S, Ritter U, Pant A, Helbich SS, Voss M, Lemmermann NA, Bessiri-Schake L, Bohn T, Eigenberger A, Menevse AN, Gebhard C, Strieder N, Abken H, Rehli M, Huehn J, Beckhove P, Hehlgans T, Junger H, Geissler EK, Prantl L, Werner JM, Schmidl C, Brors B, Imbusch CD, Feuerer M. The effector program of human CD8 T cells supports tissue remodeling. J Exp Med 2024;221(2):e20230488. doi: 10.1084/jem.20230488.
  6. Simon M, Stüve P, Schmidleithner L, Bittner S, Beumer N, Strieder N, Schmidl C, Pant A, Gebhard C, Eigenberger A, Rehli M, Prantl L, Hehlgans T, Brors B, Imbusch CD, Delacher M, Feuerer M. Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells. Immunity 2024;57(8):1975-93.e10. doi: 10.1016/j.immuni.2024.06.015. 
  7. Bittner S, Ruhland B, Hofmann V, Schmidleithner L, Schambeck K, Pant A, Stüve P, Delacher M, Echtenacher B, Edinger M, Hoffmann P, Rehli M, Gebhard C, Strieder N, Hehlgans T, Feuerer M. Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Proc Natl Acad Sci U S A 2022;119(40):e2208436119. doi: 10.1073/pnas.2208436119.
  8. Bittner S, Hehlgans T, Feuerer M. Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond. Trends Immunol 2023;44(6):468-83. doi: 10.1016/j.it.2023.04.005. 
  9. Raach B, Bundgaard N, Haase MJ, Starruß J, Sotillo R, Stanifer ML, Graw F. Influence of cell type specific infectivity and tissue composition on SARS-CoV-2 infection dynamics within human airway epithelium. PLoS Comput Biol 2023;9(8):e1011356. doi: 10.1371/journal.pcbi.1011356.
  10. Frank R, Gabel M, Heiss K, Mueller AK, Graw F. Varying Immunizations With Plasmodium Radiation-Attenuated Sporozoites Alter Tissue-Specific CD8(+) T Cell Dynamics. Front Immunol 2018;9:1137. doi: 10.3389/fimmu.2018.01137. 
  • Prof. Dr. med. Markus Feuerer
    LIT – Leibniz Institute for Immunotherapy (former RCI)
    c/o Universitätsklinikum Regensburg
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38121
    markus.feuerer@ukr.de
  • Prof. Dr. Frederik Graw
    FAU Erlangen-Nürnberg/University Hospital Erlangen
    Department of Medicine 5
    Kussmaulallee 12
    91054 Erlangen
    T: +49 9131 85-47601
    frederik.graw@fau.de

Project B09

Regulation of tissue—resident myeloid cells controlling acute and chronic GvHD
Site: Würzburg
Principal Investigator: Prof. Dr. med. Dr. med. univ. Andreas Beilhack, Dr. rer. nat. Mercedes Gomez de Agüero

Acute GvHD primarily affects the gut, liver, and skin, while sparing organs like the kidney through unclear mechanisms. We identified perivascular PD-L1hi intestinal macrophages (MPs) as key regulators of acute GvHD. While renal MPs lose PD-L1 expression following microbial priming, conditioning-induced microbial translocation rapidly recruits PD-L1+Ly6C+ monocytes that restore the renal PD-L1+ MP network. This project investigates how microbial shifts – whether induced by conditioning or through eubiotic restoration – govern organ-specific myeloid resilience, thereby suppressing GvHD while preserving GvL effects

 

1. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Pena Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022;7(22):e154250. doi: 10.1172/jci.insight.154250.  

2. Erny D, Dokalis N, Mezo C, Castoldi A, Mossad O, Staszewski O, Frosch M, Villa M, Fuchs V, Mayer A, Neuber J, Sosat J, Tholen S, Schilling O, Vlachos A, Blank T, Gomez de Agüero M, Macpherson AJ, Pearce EJ, Prinz M. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab 2021;33(11):2260-76 e7. doi: 10.1016/j.cmet.2021.10.010. 

3. Gomez de Agüero M, Ganal-Vonarburg SC, Fuhrer T, Rupp S, Uchimura Y, Li H, Steinert A, Heikenwalder M, Hapfelmeier S, Sauer U, McCoy KD, Macpherson AJ. The maternal microbiota drives early postnatal innate immune development. Science 2016;351(6279):1296-302. doi: 10.1126/science.aad2571. 

4. Jakob MO, Spari D, Sanchez Taltavull D, Salm L, Yilmaz B, Doucet Ladeveze R, Mooser C, Pereyra D, Ouyang Y, Schmidt T, Mattiola I, Starlinger P, Stroka D, Tschan F, Candinas D, Gasteiger G, Klose CSN, Diefenbach A, Gomez de Agüero M*, Beldi G.* ILC3s restrict the dissemination of intestinal bacteria to safeguard liver regeneration after surgery. Cell Rep 2023;42(3):112269. doi: 10.1016/j.celrep.2023.112269. 

5. Castelo J, Araujo-Aris S, Barriales D, Tanner Pasco S, Seoane I, Pena-Cearra A, Palacios A, Simo C, Garcia-Canas V, Khamwong M, Martin-Ruiz I, Gonzalez-Lopez M, Barcena L, Martin Rodriguez JE, Lavin JL, Gutiez N, Marcos R, Atondo E, Cobela A, Plaza-Vinuesa L, Plata A, Santos-Fernandez E, Fernandez-Tejada A, Villaran MC, Mancheno JM, Maria Flores J, Maria Aransay A, Pellon A, de Las Rivas B, Munoz R, Margolles A, Ruas-Madiedo P, Victoria Selma M, Gomez de Agüero M, Abecia L, Anguita J, Rodriguez H. The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation. Gut Microbes 2024;16(1):2438829. doi: 10.1080/19490976.2024.2438829. 

6. Obata Y, Castano A, Boeing S, Bon-Frauches AC, Fung C, Fallesen T, Gomez de Agüero M, Yilmaz B, Lopes R, Huseynova A, Horswell S, Maradana MR, Boesmans W, Vanden Berghe P, Murray AJ, Stockinger B, Macpherson AJ, Pachnis V. Neuronal programming by microbiota regulates intestinal physiology. Nature 2020;578(7794):284-9. doi: 10.1038/s41586-020-1975-8. 

7. Brandl A, Solimando AG, Mokhtari Z, Tabares P, Medler J, Manz H, Da Via MC, Croci GA, Kurzwart M, Thusek S, Schneider T, Ebert R, Jakob F, Einsele H, Beilhack A. Junctional adhesion molecule C expression specifies a CD138low/neg multiple myeloma cell population in mice and humans. Blood Adv 2022;6(7):2195-2206. doi: 10.1182/bloodadvances.2021004354. 

8. Haake M, Haack B, Schäfer T, Harter PN, Mattavelli G, Eiring P, Vashist N, Wedekink F, Genssler S, Fischer B, Dahlhoff J, Mokhtari F, Kuzkina A, Welters MJP, Benz TM, Sorger L, Thiemann V, Almanzar G, Selle M, Thein K, Späth J, Gonzalez MC, Reitinger C, Ipsen-Escobedo A, Wistuba-Hamprecht K, Eichler K, Filipski K, Zeiner PS, Beschorner R, Goedemans R, Gogolla FH, Hackl H, Rooswinkel, RW, Thiem A, Roche PR, Joshi H, Puhringer D, Wöckel A, Diessner JE, Rüdiger M, Leo E, Cheng PF, Levesque MP, Goebeler M, Sauer M, Nimmerjahn F, Schuberth-Wagner C, von Felten S, Mittelbronn M, Mehling M, Beilhack A, van der Burg SH, Riedel A, Weide B, Dummer R, Wischhusen J. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun 2023;14(1):4253. doi: 10.1038/s41467-023-39817-3. 

9. Nava Lauson CB, Tiberti S, Corsetto PA, Conte F, Tyagi P, Machwirth M, Ebert S, Loffreda A, Scheller L, Sheta D, Mokhtari Z, Peters T, Raman AT, Greco F, Rizzo AM, Beilhack A, Signore G, Tumino N, Vacca P, McDonnell LA, Raimondi A, Greenberg PD, Huppa JB, Cardaci S, Caruana I, Rodighiero S, Nezi L, Manzo T. Linoleic acid potentiates CD8(+) T cell metabolic fitness and antitumor immunity. Cell Metab 2023;35(4):633-50.e9. doi: 10.1016/j.cmet.2023.02.013. 

10. Flamann C*, Shaik H*, Matos C, Kreutz M, Ali H, Kern MAG, Büttner-Herold M, Jacobs B, Völkl S, Lischer C, Kellner C, Berges J, Bitterer K, Saul D, Goel M, L, Link-Rachner CS, Zernecke A, Weber D, Mougiakakos D, Mackensen A, Beilhack A, Bruns H. Augmented CD47 expression impairs alloreactive T cell clearance after allo-HCT. Blood 2025;2023-023056R2. doi: In press. 

Prof. Dr. med. Dr. med. univ. Andreas Beilhack

Universitätsklinikum Würzburg

Medizinische Klinik und Poliklinik II

ZEMM Zentrum für Experimentelle Molekulare Medizin

Zinklesweg 10

97078 Würzburg

T: 0931 201-44040

beilhack_a(at)ukw.de

Dr. rer. nat. Mercedes Gomez de Agüero

Julius-Maximilians-University Würzburg

Würzburg Institute für Systemimmunologie

Versbacher Straße 9

97078 Würzburg

T: +49 931 80303

mercedes.gomez(at)uni-wuerzburg.de

Project B10

Dysregulation of the B cell compartment leading to chronic GvHD Summary:
Sites: Erlangen & Regensburg
Principal Investigators: Prof. Dr. med. Fabian Müller, Prof. Dr. med. Daniel Wolff

In prior work we described elevated circulating IgA+ plasmablasts as early predictors of chronic GvHD. These plasmablasts home to the gut and produce commensal-binding IgA potentially modulating the microbiota. Aiming to identify biological processes that predict treatment response, we analyze peripheral blood and tissues for dynamic therapy-induced effects on plasmablasts and B cell trajectories, inflammatory pathways, BCR-repertoire reconstitution, and alterations of T follicular helper cells. The dynamic changes will be correlated with clinical response to standard of care and to CD19 CAR T cell therapy within a clinical trial.

  1. Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermúdez A, Kim I, Socié G, Chhabra S, Radojcic V, O’Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL, AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med 2024;391(11):1002-14. doi: 10.1056/NEJMoa2401537.
  2. Langer R, Lelas A, Rittenschober M, Piekarska A, Sadowska-Klasa A, Sabol I, Desnica L, Greinix H, Dickinson A, Inngjerdingen M, Lawitschka A, Vrhovac R, Pulanic D, Güneş S, Klein S, Moritz Middeke J, Grube M, Edinger M, Herr W, Wolff D. Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease-an analysis from transplant centers across Europe. Front Transplant 2024;3:1332181. doi: 10.3389/frtra.2024.1332181.
  3. Habenicht KM, Wanzek A, Bootz A, Schäfer S, Vollmer L, Hiergeist A, Fante M, Hasenbank J, Schneider A, Spoerl S, Brandt A, Rehli M, Hoffmann P, Wirtz S, Gerlach R, Gessner A, Mackensen A, Winkler J, Wolff D, Winkler TH. Expansions of circulating plasmablasts producing commensal-reactive IgA antibodies are predictors for chronic GVHD. Blood 2025;.doi: 10.1182/blood.2024027301 (2025).
  4. Scheidler L, Hippe K, Ghimire S, Weber D, Weber M, Meedt E, Hoffmann P, Lehn P, Burkhardt R, Mamilos A, Edinger M, Wolff D, Poeck H, Evert M, Gessner A, Herr W, Holler E. Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality. Haematologica 2023;108(11):2993-3000. doi: 10.3324/haematol.2022.282188.
  5. Schett G, Müller F, Taubmann J, Mackensen A, Wang W, Furie RA, Gold R, Haghikia A, Merkel PA, Caricchio R, D’Agostino MA, Locatelli F, June CH, Mougiakakos D. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat Rev Rheumatol 2024;20(9):531-44. doi: 10.1038/s41584-024-01139-z.
  6. Klobuch S, Weber D, Holler B, Edinger M, Herr W, Holler E, Wolff D. Long-term follow-up of rituximab in treatment of chronic graft-versus-host disease-single center experience. Ann Hematol 2019;98(10):2399-2405. doi: 10.1007/s00277-019-03768-x.
  7. Auth J, Müller F, Völkl S, Bayerl N, Distler JHW, Tur C, Raimondo MG, Chenguiti Fakhouri S, Atzinger A, Coppers B, Eckstein M, Liphardt AM, Bäuerle T, Tascilar K, Aigner M, Kretschmann S, Wirsching A, Taubmann J, Hagen M, Gyorfi AH, Kharboutli S, Krickau T, Dees C, Spörl S, Rothe T, Harrer T, Bozec A, Grieshaber-Bouyer R, Fuchs F, Kuwert T, Berking C, Horch RE, Uder M, Mackensen A, Schett G, Bergmann C. CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. Lancet Rheumatol 2025;7(2):e83-e93. doi: 10.1016/S2665-9913(24)00282-0.
  8. Liang C, Spoerl S, Xiao Y, Habenicht KM, Haeusl SS, Sandner I, Winkler J, Strieder N, Eder R, Stanewsky H, Alexiou C, Dudziak D, Rosenwald A, Edinger M, Rehli M, Hoffmann P, Winkler TH, Berberich-Siebelt F. Oligoclonal CD4(+)CXCR5(+) T cells with a cytotoxic phenotype appear in tonsils and blood. Commun Biol 2024;7(1):879. doi: 10.1038/s42003-024-06563-1.
  9. Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schafer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler TH, Krönke G, Mackensen A, Schett G. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med 2024;390(8):687-700. doi: 10.1056/NEJMoa2308917.
  10. Pelzl R BG, Gsottberger F, Scholz J K, Rübner M, Yao H, Wendland K, Rejeski K, Altmann H, Petkovic S, Mellenthin L, Kübel S, Schmiedeberg M, Klein P, Petrera A, Baur R, Eckstein S, Hoepffner-Grundy S, Röllig C, Subklewe M, Huebner H, Schett G, Mackensen A, Laurenti L, Graw F, Völkl S, Nganou-Makamdop K, Müller F. Large B-cell lymphoma imprints dysfunctional immune phenotype that persists years after treatment. Blood 2025; accepted for publication.
  • Prof. Dr. Fabian Müller
    University Hospital of Erlangen
    Department of Internal Medicine 5 – Hematology and Oncology
    Ulmenweg 18
    91054 Erlangen
    T +49 9131 85-43107
    Fabian.mueller@uk-erlangen.de
  • Prof. Dr. med. Daniel Wolff
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5531
    daniel.wolff(at)ukr.de

Project B11

Targeting the reciprocal T cell-endothelial interactions after ASCT
Site: Würzburg
Principal Investigators: Prof. Dr. med. Alma Zernecke-Madsen, Prof. Dr. med. univ. Dr. med. Andreas Beilhack

We show that endothelial cells in lymphoid organs prime alloreactive T cells in vivo and trigger lethal GvHD. Early endothelial injury increases the risks of GvHD and atherosclerosis, while VEGFR1 deficiency in endothelial cells induces an anti-inflammatory phenotype and reduces the accumulation of alloreactive T cells in the gut. We will investigate how myeloablative conditioning, ASCT, and T-cell homing affect bone marrow endothelial reconstruction and modulate T-cell responses. By studying bone marrow endothelial-immune cell interactions, we aim to develop therapeutic strategies to enhance GvL and reduce GvHD

 

  1. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI, Baker EM, Cao YA, Contag CH, Negrin RS. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 2005;106(3):1113-22. doi: 10.1182/blood-2005-02-0509.
  2. Bäuerlein CA, Riedel SS, Baker J, Brede C, Garrote AL, Chopra M, Ritz M, Beilhack GF, Schulz S, Zeiser R, Schlegel PG, Einsele H, Negrin RS, Beilhack A. A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model. BMC Med 2013;11:134. doi: 10.1186/1741-7015-11-134.
  3. Bundalo M, Vorlova S, Ulrich J, Barbieri R, Richter L, Höna L, Egg M, Bock J, Schäfer S, Solé NA, Rosa A, Rizzo G, Cochain C, Kastenmüller W, Henke E, Skryabin BV, Rozhdestvensky TS, Wildgruber M, Lorenz K, Kuhn M, Zernecke A. Redirecting full-length FLT1 expression towards its soluble isoform. promotes postischemic angiogenesis. bioRxiv 2024:2024.2009.2019.613989. doi: 10.1101/2024.09.19.613989
  4. Cochain C, Koch M, Chaudhari SM, Busch M, Pelisek J, Boon L, Zernecke A. CD8+ T Cells Regulate Monopoiesis and Circulating Ly6Chigh Monocyte Levels in Atherosclerosis in Mice. Circ Res 2015:117(3):244-53. doi: 10.1161/CIRCRESAHA.117.304611.
  5. Gil-Pulido J, Amézaga N, Jorgacevic I, Manthey HD, Rösch M, Brand T, Cidlinsky P, Schäfer S, Beilhack A, Saliba AE, Lorenz K, Boon L, Prinz I, Waisman A, Korn T, Cochain C, Zernecke A. Interleukin-23 receptor expressing gammadelta T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice. Cardiovasc Res 2022;118(14):2932-945. doi: 10.1093/cvr/cvab359.
  6. Zernecke A, Erhard F, Weinberger T, Schulz C, Ley K, Saliba AE, Cochain C. Integrated single-cell analysis based classification of vascular mononuclear phagocytes in mouse and human atherosclerosis. Cardiovasc Res 2023;119(8):1676-89. doi: 10.1093/cvr/cvac161.
  7. Zernecke A, Winkels H, Cochain C, Williams JW, Wolf D, Soehnlein O, Robbins CS, Monaco C, Park I, McNamara CA, Binder CJ, Cybulsky MI, Scipione CA, Hedrick CC, Galkina EV, Kyaw T, Ghosheh Y, Dinh HQ, Ley K. Meta-Analysis of Leukocyte Diversity in Atherosclerotic Mouse Aortas. Circ Res 2020;127(3):402-26. doi: 10.1161/CIRCRESAHA.120.316903.
  8. Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Pena Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022;7(22):e154250. doi: 10.1172/jci.insight.154250.
  9. Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM, Landan G, Herman EI, Butcher EC, Contag CH, Negrin RS. Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 2008;111(5):2919-28. doi: 10.1182/blood-2007-09-112789.
  10. Majumder S, Jugovic I, Saul D, Bell L, Hundhausen N, Seal R, Beilhack A, Rosenwald A, Mougiakakos D, Berberich-Siebelt F. Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9(+) T Cells. Front Immunol 2021;12:683631. doi: 10.3389/fimmu.2021.683631.
  • Prof. Dr. med. Alma Zernecke-Madsen
    University Hospital Würzburg
    Department of Experimental Biomedicine II
    Josef-Schneider-Straße 2
    97080 Würzburg
    T: +49 931 201-48331
    alma.zernecke(at)uni-wuerzburg.de
  • Prof. Dr. med. Dr. med. univ. Andreas Beilhack
    University Hospital Würzburg
    Department of Medicine II
    ZEMM Center for Experimental Molecular Medicine
    Zinklesweg 10
    97078 Würzburg
    T: +49 931 201-44040
    beilhack_a(at)ukw.de

Project B12

Regulation of the immune balance during ASCT by vitamin D3
Sites: Regensburg & Erlangen
Principal Investigators: Prof. Dr. rer. nat. Marina Kreutz, Dr. rer. nat. Carina Matos, Priv.-Doz. Dr. rer. nat. Heiko Bruns

We identified low vitamin D receptor (VDR) expression as an independent risk factor for mortality following ASCT. In a murine ASCT model, VDR-KO recipients showed reduced GvHD severity, likely due to elevated vitamin D3 levels modulating incoming immune cells. Myeloid cells emerged as key vitamin D3 targets and gut analyses showed VDR-dependent shifts in gene expression and microbiota. Next, we will confirm our data in an independent murine model, study VDR’s role in GvL and test local VDR agonists, including engineered probiotics producing vitamin D3 metabolites, to modulate GvHD and improve transplant outcomes.

 

 

  1. Flamann C, Peter K, Kreutz M, Bruns H. Regulation of the Immune Balance During Allogeneic Hematopoietic Stem Cell Transplantation by Vitamin D. Front Immunol 2019; 10: 2586; doi:10.3389/fimmu.2019.02586
  2. Peter K, Siska PJ, Roider T, Matos C, Bruns H, Renner K, Singer K, Weber D, Güllstorf M, Kröger N, Wolff D, Herr W, Ayuk F, Holler E, Stark K, Heid IM, Kreutz M. 1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation. Bone Marrow Transplant 2021 Feb;56(2):419-433. doi: 10.1038/s41409-020-01031-w.
  3. Bruns H, Böttcher M, Qorraj M, Fabri M, Jitschin S, Dindorf J, Busch L, Jitschin R, Mackensen A, Mougiakakos D. CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D. Leukemia 2017 Apr;31(4):985-988. doi: 10.1038/leu.2016.378.
  4. Bruns H, Büttner M, Fabri M, Mougiakakos D, Bittenbring JT, Hoffmann MH, Beier F, Pasemann S, Jitschin R, Hofmann AD, Neumann F, Daniel C, Maurberger A, Kempkes B, Amann K, Mackensen A, Gerbitz A. Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma. Sci Transl Med 2015 Apr 8;7(282):282ra47. doi: 10.1126/scitranslmed.aaa3230.
  5. Matos C, Renner K, Peuker A, Schoenhammer G, Schreiber L, Bruss C, Eder R, Bruns H, Flamann C, Hoffmann P, Gebhard C, Herr W, Rehli M, Peter K, Kreutz M. Physiological levels of 25-hydroxyvitamin D3 induce a suppressive CD4+ T cell phenotype not reflected in the epigenetic landscape. Scand J Immunol 2022 May;95(5):e13146. doi: 10.1111/sji.13146.
  6. Matos C, Peter K, Weich L, Peuker A, Schoenhammer G, Roider T, Ghimire S, Babl N, Decking S, Güllstorf M, Kröger N, Hammon K, Herr W, Stark K, Heid IM, Renner K, Holler E, Kreutz M. Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation. Front Immunol 2022 Jan 4;12:803726. doi: 10.3389/fimmu.2021.803726.
  7. Busch L, Mougiakakos D, Büttner-Herold M, Müller MJ, Volmer DA, Bach C, Fabri M, Bittenbring JT, Neumann F, Boxhammer R, Nolting J, Bisht S, Böttcher M, Jitschin S, Hoffmann MH, Balzer H, Beier F, Gezer D, Dudziak D, Gelse K, Hennig FF, Pallasch CP, Spriewald B, Mackensen A, Bruns H. Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway. Leukemia 2018 Nov;32(11):2445-2458. doi: 10.1038/s41375-018-0114-0.
  8. Matos C, Mamilos A, Shah PN, Meedt E, Weber D, Ghimire S, Hiergeist A, Gessner A, Dickinson A, Dressel R, Walter L, Stark K, Heid IM, Poeck H, Edinger M, Wolff D, Herr W, Holler E, Kreutz M, Ghimire S. Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation. Front Immunol 2022 Oct 20;13:1028850. doi: 10.3389/fimmu.2022.1028850.
  9. Schreiber L, Ghimire S, Hiergeist A, Renner K, Althammer M, Babl N, Peuker A, Schoenhammer G, Hippe K, Gessner A, Albrecht C, Pielmeier F, Büttner-Herold M, Bruns H, Hoffmann P, Herr W, Holler E, Peter K, Kreutz M, Matos C. Strain specific differences in vitamin D3 response: impact on gut homeostasis. Front Immunol 2024 Mar 1;15:1347835. doi: 10.3389/fimmu.2024.1347835. 
  10. Flamann C, Shaikh H, Matos C, Kreutz M, Ali H , Kern M, Büttner-Herold M, Jacobs B, Völkl S, Lischer C, Kellner C, Berges J, Bitterer K, Saul D, Goel M, Link-Rachner C, Zernecke A, Weber D, Mougiakakos D, Mackensen A , Beilhack A and Bruns H. Augmented CD47 expression  impairs alloreactive T cell clearance after allo-HCT. Blood 2025; accepted
  • Prof. Dr. rer. nat. Marina Kreutz
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5577
    marina.kreutz(at)ukr.de
  • PD Dr. rer. nat Heiko Bruns
    University Hospital Erlangen
    Department of Medicine 5
    Ulmenweg 18
    91052 Erlangen
    T: +49 9131 85-43163
    heiko.bruns(at)uk-erlangen.de
  • Dr. rer. nat. Carina Matos
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-38477
    carina.matos@ukr.de

Project B13

Enterococci in ASCT: Indicators of loss of diversity or true GvHD pathogens?
Site: Regensburg
Principal Investigators: Prof. Dr. med. Daniela Weber, Dr. med. Elisabeth Meedt, Prof. Dr. med. Dr. rer. nat. André Gessner

Our studies suggest a causal link between enterococci and acute GvHD. Genomic and functional analyses reveal consistent differences between enterococcal strains isolated from ASCT patients and healthy controls, as well as between GvHD and non-GvHD patients. Various strains and associated metabolites and the effects of microbiota transfer will be tested in organoid and animal models. We will also investigate the enterococci translocation into intestinal tissue and their interaction with the immune system, focusing on T and B cell responses both locally in the gut and systemically.

 

  1. Stein-Thoeringer CK, Nichols KB, Lazrak A, Docampo MD, Slingerland AE, Slingerland JB, Clurman AG, Armijo G, Gomes ALC, Shono Y, Staffas A, Burgos da Silva M, Devlin S, Markey KA, Bajic D, Pinedo R, Tsakmaklis A, Littmann ER, Pastore A, Taur Y, Monette S, Arcila ME, Pickard AJ, Maloy M, Wright RJ, Amoretti LA, Fontana E, Pham D, Jamal MA, Weber D, Sung AD, Hashimoto D, Scheid C, Xavier JB, Messina JA, Romero K, Lew M, Bush A, Bohannon L, Hayasaka K, Hasegawa Y, Vehreschild MJGT, Cross JR, Ponce DM, Perales MA, Giralt SA, Jenq RR, Teshima T, Holler E, Chao NJ, Pamer EG, Peled JU, van den Brink MRM. Lactose drives Enterococcus expansion to promote graft-versus-host disease. Science 2019; 366, 1143–1149. doi:10.1126/science.aax3760.
  2. Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, Weber D, Hashimoto D, Slingerland AE, Slingerland JB, Maloy M, Clurman AG, Stein-Thoeringer CK, Markey KA, Docampo MD, Burgos da Silva M, Khan N, Gessner A, Messina JA, Romero K, Lew MV, Bush A, Bohannon L, Brereton DG, Fontana E, Amoretti LA, Wright RJ, Armijo GK, Shono Y, Sanchez-Escamilla M, Castillo Flores N, Alarcon Tomas A, Lin RJ, Yáñez San Segundo L, Shah GL, Cho C, Scordo M, Politikos I, Hayasaka K, Hasegawa Y, Gyurkocza B, Ponce DM, Barker JN, Perales M-A, Giralt SA, Jenq RR, Teshima T, Chao NJ, Holler E, Xavier JB, Pamer EG, van den Brink MRM. Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. N Engl J Med 2020; 382, 822–834. doi:10.1056/NEJMoa1900623.
  3. Meedt E, Hiergeist A, Gessner A, Dettmer K, Liebisch G, Ghimire S, Poeck H, Edinger M, Wolff D, Herr W, Holler E, Weber D. Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation. Clin Infect Dis 2022; 74, 614–621. doi:10.1093/cid/ciab500.
  4. Thiele Orberg E*, Meedt E*, Hiergeist A*, Xue J*, Heinrich P, Ru J, Ghimire S, Miltiadous O, Lindner S, Tiefgraber M, Göldel S, Eismann T, Schwarz A, Göttert S, Jarosch S, Steiger K, Schulz C, Gigl M, Fischer JC, Janssen K-P, Quante M, Heidegger S, Herhaus P, Verbeek M, Ruland J, Van Den Brink MRM, Weber D, Edinger M, Wolff D, Busch DH, Kleigrewe K, Herr W, Bassermann F, Gessner A, Deng L, Holler E*, Poeck H*. Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation. Nat Cancer 2024; 5, 187–208. doi:10.1038/s43018-023-00669-x.
  5. Weber D, Meedt E, Poeck H, Thiele-Orberg E, Hiergeist A, Gessner A, Holler E. Fecal Microbiota Transfer in Acute Graft-versus-Host Disease following Allogeneic Stem Cell Transplantation. Visc Med 2024; 1–6. doi:10.1159/000538303.
  6. DeFilipp Z, Damania AV, Kim HT, Chang C-C, El-Jawahri A, McAfee SL, Bottoms AS, Toncheva V, Smith MM, Dolaher M, Perry L, White M, Diana B, Connolly S, Dey BR, Frigault MJ, Newcomb RA, O’Donnell PV, Spitzer TR, Mansour MK, Weber D, Ajami NJ, Hohmann E, Jenq RR, Chen Y-B. Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract. Blood Adv 2024; 8, 2074–2084. doi:10.1182/bloodadvances.2024012556.
  7. DeFilipp Z, Damania AV, Kim HT, Chang C-C, El-Jawahri A, McAfee SL, Bottoms AS, Toncheva V, Smith MM, Dolaher M, Perry L, White M, Diana B, Connolly S, Dey BR, Frigault MJ, Newcomb RA, O’Donnell PV, Spitzer TR, Mansour MK, Weber D, Ajami NJ, Hohmann E, Jenq RR, Chen Y-B. Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract. Blood Adv 2024; 8, 2074–2084. doi:10.1182/bloodadvances.2024012556
  8. Jarosch S, Köhlen J, Ghimire S, Orberg ET, Hammel M, Gaag D, Evert M, Janssen K-P, Hiergeist A, Gessner A, Weber D, Meedt E, Poeck H, D’Ippolito E, Holler E, Busch DH. Multimodal immune cell phenotyping in GI biopsies reveals microbiome-related T cell modulations in human GvHD. Cell Rep Med 2023; 4, 101125.  doi:10.1016/j.xcrm.2023.101125.
  9. Weber D, Weber M, Meedt E, Ghimire S, Wolff D, Edinger M, Poeck H, Hiergeist A, Gessner A, Ayuk F, Roesler W, Wölfl M, Kraus S, Zeiser R, Bertrand H, Bader P, Ullrich E, Eder M, Gleich S, Young R, Herr W, Levine JE, Ferrara JLM, Holler E. Reg3α concentrations at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use. Blood Adv 2023; 7, 1326–1335. doi:10.1182/bloodadvances.2022008480.
  10. Weber D, Hiergeist A, Weber M, Ghimire S, Salzberger B, Wolff D, Poeck H, Gessner A, Edinger M, Herr W, Meedt E, Holler E. Restrictive versus permissive use of broad-spectrum antibiotics in patients receiving allogeneic SCT and early fever due to cytokine release syndrome: Evidence for beneficial microbiota protection without increase of infectious complications. Clin Infect Dis 2023; ciad389. doi:10.1093/cid/ciad389.
  11. Turner AM, Li L, Monk IR, Lee JYH, Ingle DJ, Portelli S, Sherry NL, Isles N, Seemann T, Sharkey LK, Walsh CJ, Reid GE, Nie S, Eijkelkamp BA, Holmes NE, Collis B, Vogrin S, Hiergeist A, Weber D, Gessner A, Holler E, Ascher DB, Duchene S, Scott NE, Stinear TP, Kwong JC, Gorrie CL, Howden BP, Carter GP. Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin. Nature 2024. doi:10.1038/s41586-024-08095-4.
  • PD Dr. med. Daniela Weber
    University Hospital Regensburg
    Department of Internal Medicine III
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5510
    daniela.weber@ukr.de
  • Prof. Dr. med. Dr. rer. nat. André Gessner
    University Hospital Regensburg
    Department of Clinical Chemistry and Laboratory Medicine
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-6401
    andre.gessner@ukr.de

B14

Role of EGF-like growth factors in immune regulation and tissue homeostasis during GvHD
Würzburg
Prof. Dr. rer. nat. Dietmar Zaiß, Dr. rer. nat. Haroon Shaikh

The two EGF-like growth factors, Amphiregulin and HB-EGF, are strongly upregulated in their expression during GvHD and substantially influence its development and progression. It is our aim to dissect the role these factors play during the different stages of GvHD and determine how we can tailor novel approaches for the prophylaxis and treatment of GvHD, by the selective blockade or application of recombinant Amphiregulin and / or HB-EGF.

  1. du Halgouet A, Darbois A, Alkobtawi M, Mestdagh M, Alphonse A, Premel V, Yvorra T, Colombeau L, Rodriguez R, Zaiss D, El Morr Y, Bugaut H, Legoux F, Perrin L, Aractingi S, Golub R, Lantz O, Salou M. (2023) Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing. Immunity 56:78-92.
  2. Minutti CM, Modak RV, Macdonald F, Li F, Smyth DJ, Dorward DA, Blair N, Husovsky C, Muir A, Giampazolias E, Dobie R, Maizels RM, Kendall TJ, Griggs DW, Kopf M, Henderson NC, Zaiss DM*. (2019) A Macrophage-Pericyte Axis Directs Tissue Restoration via Amphiregulin-Induced Transforming Growth Factor Beta Activation. Immunity 50:645-654
  3. Minutti CM, Blair N, Schwartz C, Drube S, Kamradt T, Sibilia M, Sijts AJ, Fallon PG, Maizels RM, Zaiss DM*. (2017) Epidermal growth factor receptor expression licenses Th2 cells to function in a TCR-independent way. Immunity 47:710-722
  4. Minutti CM, Jackson-Jones LH, García-Fojeda B, Logan N, Rinqvist E, Guillamat-Prats R, Artigas A, Stamme C, Chroneos ZC, Zaiss DM, Casals C*, Allen JE.* (2017) Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver. Science 356: 1076-8
  5. Zaiss DM*, Gause WC*, Osborne LC, Artis D* (2015) Emerging functions of Amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42: 216-26
  6. Zaiss DM*., van Loosdregt J., Gorlani A., Bekker CJ., Gröne A., Sibilia M., van Bergen en Henegouwen PM., Roovers RC, Coffer PJ, Sijts AJ. (2013) Amphiregulin enhances regulatory T cell suppressive function via the epidermal growth factor receptor. Immunity 38: 275-28
  7. van Loosdregt J., Fleskens V., Tiemessen MM., van Boxtel R., Mokry M., Meerding J., Pals CE., Kurek D., Baert MR., Delemarre EM., Gröne A., Sijts AJ., Maurice MM., van Es JH., ten Berge D., Staal FJ., Zaiss DM., Prakken BJ., and Coffer PJ.* (2013) Canonical Wnt signaling negatively modulates T regulatory cell function. Immunity 39: 298-310
  8. van Loosdregt J., Fleskens V., Fu J., Brenkman AB., Bekker CJ., Pals CE., Meerding J., Berkers CR., Barbi J., Gröne A., Sijts AJ., Maurice MM., Kalkhoven E., Prakken BJ., Ovaa H., Pan F., Zaiss DM., and Coffer PJ.* (2013) USP7/HAUSP mediated stabilization of FoxP3 increases Treg suppressive capacity. Immunity 39: 259-271
  9. Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR.* (2006) Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314:1746.
  10. Schubert D, Schmidt M, Zaiss D, Jungblut P, Kamradt T.* (2002) Autoantibodies against GPI and creatine kinase in rheumatoid arthritis. Nature Immunol.  3: 411
  11. Shaikh, H. *, Helal, M., Wittmann, P., Kern, M. A. G., Abboud, Z., Gamboa Vargas, J., Pezoldt, J., Mokhtari, Z., Jarick, K., Yan, H., Müller, J. P. J., Saliba, A.-E., Riedel, A., Zernecke, A., Büttner-Herold, M., Einsele, H., Huehn, J., & Beilhack, A. * (2025). Blood Endothelial Cells Prime Alloreactive CD4+ T Cells to Initiate Acute Graft-Versus-Host Disease. bioRxiv 2025.10.07.677751; doi: https://doi.org/10.1101/2025.10.07.677751
  12. Jorgacevic, I. *, Shaikh, H. *, Ali, H., Bundalo, M., Schäfer, S., Kern, M. A. G., Büttner-Herold, M., Reu-Hofer, S., Cochain, C., Bartolomaeus, H., Saliba, A.-E., Rösch, M., Rizzo, G., Arellano Viera, E., Gamboa Vargas, J., Berberich-Siebelt, F., Herr, W., Boon, L., Rosenwald, A., Butt, E., Hermanns, H., Beilhack, A., & Zernecke, A. (2025). Allogeneic hematopoietic cell transplantation initiates atherosclerosis in mice via CD8+ T cells. Cardiovascular Research, 2025 Dec 31;121(17):2668-2678.
  14. Flamann, C. *, Shaikh, H. *, Matos, C., Kreutz, M., Ali, H., Kern, M. A. G., Büttner-Herold, M., Jacobs, B., Völkl, S., Lischer, C., Kellner, C., Berges, J., Bitterer, K., Saul, D., Goel, M., Link-Rachner, C. S., Zernecke, A., Weber, D., Mougiakakos, D., Mackensen, A., Beilhack, A., & Bruns, H. (2025). Augmented CD47 expression impairs alloreactive T cell clearance after allo-HCT. Blood. 2025 Sep 11;146(11):1359-1373.
  16. Daud, M., Dasari, P., Adelfinger, M., Langenhorst, D., Lother, J., Slavkovic-Lukic, D., Berges, C., Kruhm, M., Galler, A., Schleussner, C., Luther, C. H., Alberter, K., Althammer, A., Shaikh, H., Pallmann, N., Bodem, J., El‐Mowafy, M., Beilhack, A., Dittrich, M., Topp, M. S., Zipfel, P. F., & Beyersdorf, N. (2023). Enolase 1 of Candida albicans binds human CD4⁺ T cells and modulates naïve and memory responses. European Journal of Immunology, 53(11), e2250284.
  18. Mueller, J. P. J., Dobosz, M., O’Brien, N., Abdoush, N., Giusti, A. M., Lechmann, M., Osl, F., Wolf, A.-K., Arellano-Viera, E., Shaikh, H., Sauer, M., Rosenwald, A., Herting, F., Umaña, P., Colombetti, S., Pöschinger, T., & Beilhack, A. (2023). ROCKETS – A novel one-for-all toolbox for light sheet microscopy in drug discovery. Frontiers in Immunology, 2023 Feb 7:14:1034032.
  19.  
  20. Shaikh, H., Pezoldt, J., Mokhtari, Z., Vargas, J. G., Le, D., Mosca, J. P., Viera, E. A., Kern, M. A., Graf, C., Beyersdorf, N., Lutz, M. B., Riedel, A., Büttner-Herold, M., Zernecke, A., Einsele, H., Saliba, A., Ludewig, B., Huehn, J., & Beilhack, A. (2022). Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight. 2022 Nov 22;7(22):e154250.
  21.  
  22. Ataide, M. A. *, Knöpper, K. *, De Casas, P. C. *, Ugur, M., Eickhoff, S., Zou, M., Shaikh, H., Trivedi, A., Grafen, A., Yang, T., Prinz, I., Ohlsen, K., De Agüero, M. G., Beilhack, A., Huehn, J., Gaya, M., Saliba, A., 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.
  24. Vargas, J. G. *, Wagner, J. *, Shaikh, H., Lang, I., Medler, J., Anany, M., Steinfatt, T., Mosca, J. P., Haack, S., Dahlhoff, J., Büttner-Herold, M., Graf, C., Viera, E. A., Einsele, H., Wajant, H., & Beilhack, A. (2022). A TNFR2-Specific TNF fusion protein with improved in vivo activity. Frontiers in Immunology, 13. 2022 Jun 13:13:888274.
  25.  
  26. Shaikh, H., Vargas, J. G., Mokhtari, Z., Jarick, K. J., Ulbrich, M., Mosca, J. P., Viera, E. A., Graf, C., Le, D., Heinze, K. G., Büttner-Herold, M., Rosenwald, A., Pezoldt, J., Huehn, J., & Beilhack, A. (2021). Mesenteric lymph node transplantation in mice to study immune responses of the gastrointestinal tract. Frontiers in Immunology, 2021 Jul 26:12:689896.
  27.  
  28. Ranjan, S., Goihl, A., Kohli, S., Gadi, I., Pierau, M., Shahzad, K., Gupta, D., Bock, F., Wang, H., Shaikh, H., Kähne, T., Reinhold, D., Bank, U., Zenclussen, A. C., Niemz, J., Schnöder, T. M., Brunner-Weinzierl, M., Fischer, T., Kalinski, T., Schraven, B., Luft, T., Huehn, J., Naumann, M., Heidel, F. H., Isermann, B. (2017). Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. Nature Communications, . 2017 Aug 21;8(1):311.

 

 

  • Prof. Dr. Dietmar M.W. Zaiss
    University Regensburg, Faculty of Medicine
    Department of Immune Medicine,
    Professor for Immune Cell Communication
    Franz-Josef-Strauß-Allee 11
    93053 Regensburg
    T: +49 941 944-5466
    dietmar.zaiss@ukr.de
  • Dr. rer. nat. Haroon Shaikh
    University Hospital Würzburg
    Department of Medicine II
    Zinklesweg 10
    97078 Würzburg
    T: +49 931 201-44050
    shaikh_h@ukw.de

B15

Elucidating inflammatory remodeling of the bone marrow niche after ASCT
Würzburg
Prof. Dr. rer. nat. Dominic Grün, Priv.-Doz. Dr. med. Sabrina Kraus

Severe acute (a)GvHD is associated with long-lasting hematopoietic dysfunction, yet the underlying mechanisms remain unknown. We hypothesize that perturbed bone marrow niche interactions of HSCPs after ASCT impair regeneration of hematopoiesis in aGvHD. Using single-cell RNA-sequencing and spatial transcriptomics, we will reconstruct the spatial bone marrow architecture in patients with severe aGvHD, and compare between steroid-refractory and -responsive groups. By inferring perturbations of the bone marrow niche and underlying molecular pathways, we will identify key local cellular interactions contributing to BM failure.

  1. Chan ASF, Greiner J, Marschh√§user L, Brennan TA, Perez-Feliz S, Agrawal A, Hemmer H, Sinning K, Cheung WL, Iqbal Z, Klesen A, Vico TA, Aprea J, Hilgendorf I, Seidel T, Vaeth M, Rog-Zielinska E, Kohl P, Schneider-Warme F, Grün D (2025) Spatio-temporal dynamics of the fibrotic niche in cardiac repair. Nature Cardiovascular Research. 2025;4(11): 1550-1572. doi:10.1038/s44161-025-00739-6.
  2. Agrawal A, Thomann T, Basu S, Grün D. NiCo Identifies Extrinsic Drivers of Cell State Modulation by Niche Covariation Analysis. Nature Communications.2024; 15(1):10628. doi: 10.1038/s41467-024-54973-w
  3. Rosales-Alvarez RE, Rettkowski J, Herman JS, Dumbović G, Cabezas-Wallscheid N, Grün D. VarID2 quantifies gene expression noise dynamics and unveils functional heterogeneity of ageing hematopoietic stem cells. Genome Biology. 2023; 24(1):148. doi: 10.1186/s13059-023-02974-1
  4. Nusser A, Sagar, Swann JB, Krauth B, Diekhoff D, Calderon L, Happe C, Grün D#, Boehm T#. Developmental dynamics of two bipotent thymic epithelial progenitor types. 2022; 606(7912):165-171. doi: 10.1038/s41586-022-04752-8
  5. Zeis P, Lian M, Fan X, Herman JS, Hernandez DC, Gentek R, Elias S, Symowski C, Knöpper K, Peltokangas N, Friedrich C, Doucet-Ladeveze R, Kabat AM, Locksley RM, Voehringe D, Bajenoff M, Rudensky AY, Romagnani C, Grün D#, Gasteiger G#. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors. Immunity. 2020; 53(4):775-792.e9. doi: 1016/j.immuni.2020.09.002
  6. Sagar, Pokrovskii M, Herman JS, Naik S, Sock E, Lausch U, Wegner M, Tanriver Y, Littman DR, Grün D. Deciphering the Regulatory Landscape of γδ T Cell Development by Single-Cell RNA-Sequencing. EMBO Journal. 2020; 39(13): e104159. doi: 10.15252/embj.2019104159
  7. Grün D. Revealing Dynamics of Gene Expression Variability in Cell State Space. Nature Methods. 2020; 17(1): 45-49. doi: 10.1038/s41592-019-0632-3
  8. Aizarani A, Saviano A, Sagar, Mailly L, Durand S, Herman JS, Pessaux P, Baumert TF#, Grün D#. A Human Liver Cell Atlas reveals Heterogeneity and Epithelial Progenitors. 2019; 572(7768): 199-204. doi: 10.1038/s41586-019-1373-2
  9. Herman JS, Sagar, Grün D. FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. Nature Methods. 2018; 15(5): 379-386. doi: 10.1038/nmeth.4662
  10. Grün D, Lyubimova A, Kester L, Wiebrands K, Basak O, Sasaki N, Clevers H, van Oudenaarden A. Single-cell mRNA sequencing reveals rare intestinal cell types. Nature. 2015; 525: 251-255. doi: 10.1038/nature14966
  11. Wermke M, Kraus S, Ehninger A, Bargou RC, Goebeler ME, Middeke JM, Kreissig C, von Bonin M, Koedam J, Pehl M, Bornhäuser M, Einsele H, Ehninger G, Cartellieri M. Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood 2021;137(22):3145–8. doi.org/10.1182/blood.2020009759.
  12. Lauruschkat CD, Muchsin I, Rein AF, Erhard F, Grathwohl D, Dölken L, Köchel C, Nehmer A, Falk CS, Grigoleit GU, Einsele H, Wurster S, Kraus S. Impaired T cells and “memory-like” NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation. Blood Adv 2024;8(11):2967–79. doi.org/10.1182/bloodadvances.2023012008.
  13. Rein AF, Lauruschkat CD, Muchsin I, Köchel C, Tischer-Zimmermann S, Bauersfeld L, Nelde A, Lübke M, Prusty BK, Schlosser A, Halenius A, Eiz-Vesper B, Dölken L, Grigoleit GU, Einsele H, Erhard F, Kraus S. Identification of novel canonical and cryptic HCMV-specific T-cell epitopes for HLA-A∗03 and HLA-B∗15 via peptide-PRISM. Blood Adv 2024;8(3):712–24. doi.org/10.1182/bloodadvances.2023011120
  14. Lauruschkat CD, Görge H, Knies K, Weißbrich B, Dölken L, Köchel C, Imhof N, Huber M, Hengel H, Einsele H, Wurster S, Kraus S. Human cytomegalovirus control in allogeneic stem cell transplant recipients in the letermovir era – emerging humoral and cellular players. Haematologica. 2025 Nov 27. doi: 10.3324/haematol.2025.288237.
  • Prof. Dr. rer. nat. Dominic Grün
    Institute of Systems Immunology
    Julius-Maximilians-Universität Würzburg
    Versbacher Str. 9
    97078 Würzburg
    Tel.: +49 931 31-81481
    dominic.gruen@uni-wuerzburg.de
  • PD Dr. med. Sabrina Kraus
    University Hospital Würzburg
    Department of Internal Medicine II
    Oberdürrbacher Straße 6
    97080 Würzburg
    T: +49 931 201-40967
    Kraus_S3@ukw.de

Spokespersons

Within the Collaborative Research Centre/Transregio (CRC/TRR) 221 innovative immune modulation strategies will be investigated to separate GvHD from GvL effects in order to enhance the safety and efficacy of allo-HSCT in the future.

Andreas Mackensen

Wolfgang Herr

Hermann Einsele

PARTICIPATING INSTITUTIONS

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UE
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Contact us
Tel: (0049) 0941 944 - 5501
Fax: (0049) 0941 944 - 5502
Mail: wolfgang.herr(at)ukr.de
93053 Regensburg,
Franz-Josef-Strauß-Allee 11
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